I

EVALUATION OF THE REGULATORY REVIEW PROCESS OF

THE GCC CENTRALISED PROCEDURE: DEVELOPMENT OF

A MODEL FOR IMPROVING THE APPROVAL PROCESS

A thesis submitted in accordance with the condition

governing candidates for the degree of

DOCTOR OF PHILOSOPHY

in

CARDIFF UNIVERSITY

Presented by

MOHAMMED HAMDAN AL-RUBAIE

2013

II

DECLARATION

This work has not been submitted in substance for any other degree or award at this or any

other university or place of learning, nor is being submitted concurrently in candidature for any

degree or other award.

Signed (candidate) Date 27-11-2013

STATEMENT 1

This thesis is being submitted in partial fulfillment of the requirements for the degree of PhD

(insert MCh, MD, MPhil, PhD etc, as appropriate)

Signed (candidate) Date 27-11-2013

STATEMENT 2

This thesis is the result of my own independent work/investigation, except where otherwise

stated.

Other sources are acknowledged by explicit references. The views expressed are my own.

Signed (candidate) Date 27-11-2013

STATEMENT 3

I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter-

library loan, and for the title and summary to be made available to outside organisations.

Signed (candidate) Date 27-11-2013

STATEMENT 4: PREVIOUSLY APPROVED BAR ON ACCESS

I hereby give consent for my thesis, if accepted, to be available for photocopying and for inter-

library loans after expiry of a bar on access previously approved by the Academic

Standards & Quality Committee.

Signed (candidate) Date 27-11-2013

III

IV

ACKNOWLEDGEMENTS

I am greatly indebted to my supervisors, Prof Sam Salek and Prof Stuart Walker for

their outstanding supervision and expert advice and guidance throughout, and for their

continuous encouragement and ultimate support throughout the preparation of this

thesis.

Thanks also go to all the staff at the School of Pharmacy and pharmaceutical sciences,

especially Helen Harron and Justine Jenkins who assisted me throughout the study.

I would also like to express my gratitude and appreciation to my colleagues in the

Health authorities in the Gulf States and in the Executive Board of the Health Ministers

Council for GCC States, without whose input in terms of data provision, it would not

have been possible to conduct this research.

I dedicate my thesis to my family, especially my parents, my loving wife, my kids,

,brothers and sisters, I would like to thank them for their encouragement, support and

love. Their belief in me gave me the strength to pursue my research successfully.

V

ABSTRACT

The aim of this study was to evaluate seven GCC regulatory authorities and pharmaceutical

companies active in the region in order to identify the strengths and weakness of the current

GCC centralised procedure. The GCC regulatory authorities and the pharmaceutical companies

who had registered their products through the GCC centralized registration procedure and the

national registration systems were recruited into the study and asked to complete the

questionnaires specifically designed for this study.

The regulatory review process in Oman was evaluated to identify areas for improvement in the

system. Information on the total application numbers and approval dates were obtained directly

from the Oman Ministry of Health archives. Another study was conducted to evaluate the

regulatory review process and approval times of the remaining six GCC countries (Bahrain,

Kuwait, Qatar, Saudi Arabia, UAE and Yemen) and the GCC central registration, with respect to

review time for new and existing substances, to identify the strengths and weaknesses of the

process and to propose strategies that could help the policy maker in the GCC to enhance the

review process.

The results of the Omani regulatory system showed no significant increase (p>0.05) in the total

number of registered pharmaceutical products from 2006 to 2010. The approval time in Oman

showed that there was a significant increase in approval times for pharmaceutical products from

2006 to 2010 (p<0.001). The findings show that although there was an increase in the approval

time for all pharmaceutical company products, the median approval time for the five year period

was 117 days. This was within the time limit (4 months) fixed by the health authority for the

overall registration time. The comparative study of the GCC States showed a downward trend in

the median approval time for most of the GCC States, during 2008 to 2010. However, the

approval time for all approved products in the GCC States during this period varied from 60

days in Qatar and Oman (2009 and 2010) to 609 days in Saudi Arabia (2008). The main

reasons for the decrease in approval time in the Gulf States were due to the positive effect of

the Gulf Central Registration, the rise in the number of reviewers in some GCC drug authorities,

and the parallel procedure used in the regulatory approval review process. The study of the

regulatory review process of the GCC central registration showed that a total of 413 products

(96 NASs and 317 EASs) were approved during the period 2006-2010 with an overall significant

increase in the EASs (p<0.001). The approval times increased from 107 calendar days in 2006

to 265 in 2010 (p<0.001). The lowest approval time was for EASs submitted by the Gulf

companies (134 days) and the longest for NASs submitted by international companies (346

days) (p<0.001).

VI

Both the regulatory authorities and the pharmaceutical companies agreed that the centralised

procedure is an effective system for authorising medicinal products in all seven GCC countries

in one procedure and is the way forward in the future but there is room for improvement in the

procedure and the follow ups. They also agreed that clear guidelines, transparency of

procedures, effective interactions between authorities and companies, increase in the number

of the committee meetings per year, use of electronic on-line submissions will improve approval

time for registration of new medicines, enhance the quality of review practice and encourage

the pharmaceutical companies to use the GCC central registration system. This research has

enabled development of a new model of the GCC central registration procedure to be proposed

for the GCC Health Authorities which could improve patient access to medicines in the GCC

states.

VII

TABLE OF CONTENTS

Acknowledgements …………………………………………………………………… IV

Abstract ………………………………………………………………………………. V

Table of contents …………………………………………………………………….. VII

Glossary of abbreviations …………………………………………………………… IX

Glossary of terms ……………………………………………………………………. XI

List of figures ………………………………………………………………………… XVI

List of tables ………………………………………………………………………….. XIX

Chapter one……………………………………………………………………………. 1

Background………………………………………………………………………….. 2

Regulatory Reviews Process, Approval Times and Patients' Access to Medicines 2

Quality of the Review Process …………………………………………………… 5

Benefit-risk assessment and decision-making …………………………………… 7

Role of harmonisation ……………………………………………………………. 8

The Gulf Cooperation Council (GCC) States ……………………………………. 9

GCC Drug Regulatory Authorities ………………………………………………. 10

Evolution of GCC-DR …………………………………………………………… 11

The quality of the review in the GCC …………………………………………… 15

Global drug development and its influence on the regulatory environment in the Gulf

Region ……………………………………………………………………………. 16

Aims and objectives of the study ………………………………………………….. 18

Chapter two ……………………………………………………………………….... 19

Study rationale & methodological framework

Rational of the study …………………………………………………………….... 20 Methodology framework …………………………………………………………. 21

Development of the Study Plan ………………………………………………..... 31

Development of the Study Instruments ………………………………………….... 33

Data processing and analysis …………………………………………………... … 35

Summary ………………………………………………………………………….. 40

Chapter three ……………………………………………………………………… 41

Evaluation of the Pharmaceutical Regulatory Review Process in Oman

Introduction ……………………………………………………………………… 42 Objectives ……………………………………………………………………….. 43

Methods …………………………………………………………………………. 43 Results …………………………………………………………………………... 44 Discussion ………………………………………………………………………. 61 Conclusion ……………………………………………………………………… 65 Summary ………………………………………………………………………… 66

Chapter four ………………………………………………………………………. 67

Evaluation of Regulatory Review Times in the Gulf States

Introduction ……………………………………………………………………… 68 Objectives ……………………………………………………………………….. 69

Methods …………………………………………………………………………. 69 Results …………………………………………………………………………… 70

VIII

Discussion ………………………………………………………………………….. 90

Summary …………………………………………………………………………… 95 Chapter five …………………………………………………………………………... 96

An Evaluation of the GCC Centralised Regulatory Review Process

Introduction ………………………………………………………………………… 97

Objectives ………………………………………………………………………….. 98 Methods ……………………………………………………………………………. 99

Results ……………………………………………………………………………... 101

Discussion …………………………………………………………………………. 112

Summary …………………………………………………………………………... 115

Chapter six …………………………………………………………………………... 117

An Evaluation of the Gulf States Views and Experiences with GCC Centralised Procedure

Introduction ………………………………………………………………………… 118

Objectives ………………………………………………………………………….. 119

Methods ……………………………………………………………………………. 119

Results ……………………………………………………………………………... 119

Discussion …………………………………………………………………………. 147

Summary …………………………………………………………………………... 150

Chapter seven ………………………………………………………………………… 152

An Evaluation of the Pharmaceutical Companies Experiences with the GCC Centralised

Procedure

Introduction ………………………………………………………………………... 153

Objectives ………………………………………………………………………….. 154

Methods ……………………………………………………………………………. 154

Results ……………………………………………………………………………... 155

Discussion ………………………………………………………………………………... 183

Summary …………………………………………………………………………………. 187

Chapter eight ………………………………………………………………………... 188

The Gulf Centralised Procedure- A Comparison between the Experiences of Regulatory

Authorities and Pharmaceutical Companies, a proposed new model

Introduction ……………………………………………………………………….. 189

Objectives ………………………………………………………………………… 190

Methods …………………………………………………………………………… 190

Results &Discussion …………………………………………………………………… 191

Summary ………………………………………………………………………………… 209 Chapter nine ………………………………………………………………………... 210

General Discussion

Limitation of the study …………………………………………………………… 219 Recommendations ……………………………………………………………..... 220 Future work ……………………………………………………………………… 223 Conclusion ……………………………………………………………………..... 224

References …………………………………………………………………………. 225

Publications ……………………………………………………………………….. 237

Appendix……………………………………………………………………………. 239

IX

LIST OF ABBREVIATIONS

AMRH: African Regulatory Harmonization Initiative

APEC: Asia Pacific Economic Cooperation

ADEC: Australian Drug Evaluation Committee.

ATC: Anatomical Therapeutic and Chemical code.

CACP: Companies Assessment of Central Procedure

CATI: Computer assisted telephone interviewing

CBER: Centre for Biologics Evaluation and Research.

CIF: Cost, Insurance and Freight

CIRS: Centre for Innovation in Regulatory Science

CDER: Centre for Drug Evaluation and Research.

CLADF: Central Laboratory for Analysis of Drugs and Food.

CTD: Centralised Technical Document

CHMP: Committee for Medicinal Products for Human Use.

CMR: Centre for Medicines Research

CPP: Certificate of Pharmaceutical Product.

DGPA&DC: Directorate General of Pharmaceutical Affairs and Drug Control

EMA: European Medicines Agency.

EU: European Union.

FDA: Food and Drug Administration.

GACP: Gulf Assessment of Centralised Procedure

GCC: Gulf Cooperation Council

GCC-CP: Gulf Cooperation Council Centralised Procedure

GCC-DR: Gulf Cooperation Council Drug Registration committee.

GCP: Good Clinical Practice.

GRP: Good Review Practice.

HAS: Health Sciences Authority of Singapore.

ICH: International Conference on Harmonisation.

IND: Investigational New Drug.

IT: Information Technology.

KSA: Kingdom of Saudi Arabia.

MA: Marketing Authorisation.

MCA: Medicines Control Agency.

X

MEB: Medicines Evaluation Board.

MERC: Middle East Regulatory Conference.

MERCOSUR: Mercado Comundel Sur

MHLW: Ministry of Health, Labour and Welfare.

MHW: Ministry of Health and Welfare.

MPA: Medical Products Agency.

NAS: New Active Substance.

NCE: New Chemical Entity.

NDA: New Drug Application.

NME: New Molecular Entity.

NGT:Nominal Group Technique

OCD: Office Centre Director.

PD: Pharmacodynamics.

PDUFA: Prescription Drug User Fee Act.

PANDRH:Pan American Network for Drug Regulatory Harmonisation

PK: Pharmacokinetics.

PMS: Post Marketing Surveillance.

PPRS: Pharmaceutical Pricing Regulation Scheme.

QA: Quality Assurance.

QCL: Quality Control Laboratory

R&D: Research and Development.

RC: Registration Committee.

RMS: Reference Member State.

SADC: Southern African Development Community

SOP: Standard Operating Procedure.

TCR&P: Technical Committee for Registration of Pharmaceutical Manufacturers & Their

Products & Pricing

TGA: Therapeutics Goods Administration.

TRIPS: Trade-Related Aspects of Intellectual Property Rights.

UAE: United Arab Emirates.

WHO: World Health Organisation.

WTO: World Trade Organisation.

XI

GLOSSARY OF TERMS

Adverse event: Any untoward medical occurrence in a patient or clinical investigation of a subject

administered a pharmaceutical product and which does not necessarily have a causal relationship

with this treatment.

Africa, the Southern African Development Community (SADC): Angola, Botswana, Democratic

Republic of Congo, Lesotho, Malawi, Mauritius, Mozambique, Namibia, Seychelles, South Africa,

Swaziland, Tanzania, Zambia and Zimbabwe.

Approval: The active substance has been approved for licence by a regulatory authority in one or

more markets (when the authority grants a licence and subject to pricing/ reimbursement issues the

product can be legally marketed).

Arab Central Registration (ACR): Jordan, UAE, Bahrain, Tunisia, Algeria, Djibouti, KSA, Sudan,

Syria, Somalia, Iraq, Oman, Palestine, Mauritania, Yemen, Qatar, Comoros, Kuwait, Lebanon,

Libya, Egypt and Morocco.

Asia-Pacific Economic Cooperation (APEC): Australia, Brunei Darussalam, Canada, Chile, China,

Hong Kong, Indonesia, Japan, South Korea, Malaysia, Mexico, New Zealand, Papua New Guinea,

Peru, Philippines, Russia, Singapore, Taiwan, Thailand, USA and Vietnam.

Association of Southeast Asian Nations (ASEAN): Brunei, India, Thailand, Philippines, Indonesia,

Malaysia, Singapore, Myanmar and Cambodia.

Benefit/risk ratio: The benefit to risk ratio relates the potential or actual benefit that a patient

derives from a treatment to the risks incurred by the patient through using the treatment. The benefit

to risk ratio can be described in qualitative terms (high, low, equal, very low etc).

Binding: Advice provided by a regulatory authority prior to submission that is acknowledged and

considered a regulatory agreement.

Biological: A substance isolated from animal tissues e.g. vaccines, hormones, antigens.

Biotech product: A naturally occurring or modified polypeptide, protein, DNA or RNA product

(produced by recombinant DNA or hybridoma technology and expressed in cell lines, transgenic

animals or transgenic plants) for therapeutic, prophylactic or in vivo diagnostic use in humans. The

only types of vaccines included in the biotech category are recombinant vaccines.

XII

Centralised procedure: The Centralised procedure is used when marketing authorization

covering the entire EU region is applied for, for example, for new biotechnological medicinal

products and new innovative medicinal products. The applications for marketing authorization

are then submitted to the European Agency for the Evaluation of Medicinal Products (EMEA).

Clinical trial: Any investigation in human subjects intended to discover or verify the clinical,

pharmacological and/or other pharmacodynamic effects of an investigational product, and/or to

identify any adverse reactions to an investigational product, and/or to study the absorption,

distribution, metabolism and excretion of an investigational product, with the objective of

ascertaining its safety and/or efficacy.

Collaborative or sponsored research: The active substance is discovered as a result of research

carried out in collaboration with, or sponsored by, another company, a university, government

agency or an individual.

Co-operation Council of the Arab Gulf States (GCC): Bahrain, Kuwait, Oman, Qatar, United

Arab Emirates and the Kingdom of Saudi Arabia.

Drug product: A finished formulation, for example, a tablet or capsule that contains the active

substance, generally in association with one or more other ingredients.

Drug Regulatory Authority (DRA): The agency that develops and implements most of the

legislation and regulation of medicines.

European Union Member States (EU): Austria, Belgium, Cyprus, Czech Republic, Denmark,

Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania,

Luxembourg, Malta, Poland, Portugal, Slovakia, Slovenia, Spain, Sweden The Netherlands and

the United Kingdom.

Extrapolation of foreign clinical data: The generalisation and application of the safety,

efficacy and dose response data generated in a population of a foreign region to the population of

the new region.

Foreign region: Any region outside the new region where product authorisation is being sought.

ICH Regions: European Union, Japan and USA.

ICH: International Conference on Harmonisation.

XIII

Indication: The specific indication for which the active substance for the project is designed.

This may represent the cure, alleviation, treatment, prevention or diagnosis of disease in humans.

Investigational New Drug (IND): An application that a drug sponsor must submit to FDA

before beginning tests of a new drug in humans. The IND contains the plan for the study and is

supposed to give a complete picture of the drug, including structural formula, animal test results,

and manufacturing information.

Launched: The active substance is made available for sale as an ethical prescription only

medicine in the first market in any country.

Line extension: NASs which are already marketed but are being further developed for new

indications, formulations, dosages, routes of administration, or novel drug delivery systems.

Local study: A study conducted in a single country with the primary aim of providing local

experience with a compound.

Marketing Authorisation (MA): Legal approval granted to a company by a national (or

regional) authority to market a medicinal product in that particular country (or region).

Marketing Authorisation Application (MAA): An application by a company for a marketing

authorisation to be submitted to each country (or region) in which marketing approval is sought.

Mutual Recognition procedure: The Mutual Recognition (MR) procedure utilizes the

marketing authorization granted for an active substance by another EU Member State, Norway,

or Iceland. The Member State whose assessment is recognized as a basis for marketing

authorization is called the Reference Member State (RMS).

National procedure: The national procedure is mainly used in cases where marketing

authorisation is being applied for in a single member state within the.

New Active Substance (NAS): A chemical, biological or radiopharmaceutical substance not

previously authorised as a medicinal product. The term NAS also includes: an isomer, mixture of

isomers, a complex or derivative or salt of a chemical substance previously authorised as a

medicinal product but differing in properties with regard to safety and efficacy from that

substance previously authorised; a biological substance previously authorised as a medicinal product,

but differing in molecular structure, nature of source material or manufacturing process; a

radiopharmaceutical substance that is a radionuclide or a ligand not previously authorised as a

XIV

medicinal product. Alternatively, the coupling mechanism linking the molecule and the radionuclide

that has not been previously authorised.

New Chemical Entity (NCE): An entity produced by chemical synthesis.

New Drug Application (NDA): An application requesting regulatory approval to commercially

market a new drug for human use.

New Molecular Entity (NME): A product (including new chemical entities, biological products,

vaccines and products of biotechnology) that has not been previously available for therapeutic use in

man and is destined to be made available as a „prescription-only medicine‟, to be used for the cure,

alleviation, treatment, prevention or in vivo diagnosis of diseases in man. New salts, pro drugs and

esters of existing products and certain biological compounds (e.g. antigens) are excluded.

Combination products are also excluded unless one or more of the active constituents has never been

previously marketed.

Pan-America Network for Drug Regulatory Harmonisation (PANDRA): Mexico, Costa Rica,

Trinidad, Argentina and Colombia.

Pharmacodynamics (PD): Involves the study of the effect that a drug has on the body. This will

include looking at what effect the amount of drug has, called a dose response, and will also look at

the site of action of the drug, such as the kinetics of how a drug interacts with a receptor.

Pharmacogenetics: is the study of interindividual variations in DNA sequence related to drug

response.

Pharmacogenomics: is the study of the variability of the expression of individual genes relevant to

disease susceptibility as well as drug response at cellular, tissue, individual or population level. The

term is broadly applicable to drug design, discovery, and clinical development.

Pharmacokinetics (PK): Involves the study of the manner in which the body handles a drug. It

looks at the rate at which drug concentrations change in the body, and is involved with analysing the

kinetics of absorption, distribution, metabolism and excretion of a drug.

Phase I: Initial safety trials on a new medicine, usually conducted in normal male volunteers. An

attempt is made to establish the dose range tolerated by volunteers for single and multiple doses.

Phase I trials are sometimes conducted in severely ill patients (e.g. in the field of cancer) or in less ill

patients (e.g. metabolism of a new antiepileptic medicine in stable epileptic patients whose

microsomal liver enzymes have been induced by other epileptic medicines). Pharmacokinetic trials

XV

are usually considered Phase I trials regardless of when they are conducted during the development

of medicines.

Phase II: Clinical trials (pilot and well-controlled) to evaluate efficacy (and safety) in patients with

the disease or condition to be treated, diagnosed, or prevented. Objectives may focus on dose-

response, type of patient, frequency of dosing, or numerous other characteristics of safety and

efficacy.

Phase III: Clinical trials conducted in patient populations for which the medicine is eventually

intended. These generate additional data on both safety and efficacy in relatively large numbers of

patients, in both controlled and uncontrolled trials. Clinical trials are also conducted in special

groups of patients (e.g. renal failure patients) or under special conditions dictated by the nature of the

medicine and disease. These trials often provide much of the information needed for the package

insert and labelling of the medicine and also include trials that are conducted after the regulatory

submission of a new drug application or other dossier, but prior to the medicine‟s approval and

launch.

Phase IV: Phase IV clinical trials are (other than routine surveillance) performed after drug approval

and related to the approved indication. They are not considered necessary for approval but are often

important for optimising the drug‟s use. They may be of any type but should have valid scientific

objectives. Commonly conducted studies include additional drug-drug interaction, dose-response, or

safety studies and studies designed to support an extended claim under the approved indication, e.g.,

mortality/morbidity studies.

Pivotal study: Well-controlled trial to evaluate efficacy (and safety) in patients with the disease or

condition to be treated, diagnosed, or prevented. These clinical trials usually represent the most

rigorous demonstration of a medicine‟s efficacy.

Preclinical: In vivo and in vitro studies to support administration to man.

Pre-submission: The last patient visit for the last pivotal study to be included in the regulatory

dossier is complete and the dossier is being prepared but has not yet been submitted to a regulatory

authority.

Reference Member State (RMS): The EU member state that is chosen by a company to conduct the

first review in the EU for marketing authorisation through the Mutual Recognition procedure.

XVI

LIST OF FIGURES

Figure 1.1

Regulatory approval times from date of submission to date of approval for

New Active Substances (NASs) approved 2007-2011

4

Figure 1.2 Number of NASs approved by ICH agencies (EMA, FDA, PMDA)

by approval year (2003-2012)

4

Figure 1.3 Median approval time of NASs approved by ICH agencies (2003-2012) 5

Figure 1.4 The Eight Step of the Benefit Risk Framework 8

Figure 1.5 Map of the seven Gulf Cooperation Council (GCC) States 10

Figure 2.1 Adoption of the Dolphi approach to be used in this study 31

Figure 3.1 Process map for sultanate of Oman 46

Figure 3.2 Total number of pharmaceutical products approved in Oman (2006-2010) 49

Figure 3.3 Number of EASs approved in Oman for the period (2006-2010) 50

Figure 3.4 Number of NASs approved in Oman for the period (2006-2010) 51

Figure 3.5 Approved pharmaceutical products (EASs & NASs) for GCC, international,

non-GCC Arab and Asian companies (2006-2010)

52

Figure 3.6 Median approval time for all pharmaceutical products in Oman (2006-2010) 53

Figure 3.7 Median approval time for Existing Active Substance (EASs) in Oman

(2006-2010)

53

Figure 3.8 Median approval time for NASs in Oman (2006-2010) 54

Figure 3.9 Median approval time for GCC, international, non-GCC Arab, and Asian

companies Existing Active Substances (EASs) in Oman (2006-2010).

55

Figure 3.10 Median approval time for different dosage forms for EASs and NASs in

Oman, (2006-2010)

56

Figure 3.11 Median approval times for different therapeutic classes for EASs and NASs

in Oman (2006-2010) 57

Figure 4.1 Process map for Bahrain 72

Figure 4.2 Process map for Kuwait 73

Figure 4.3 Process map for Oman 74

Figure 4.4 Process map for Qatar 75

Figure 4.5 Process map for Kingdom of Saudi Arabia 76

Figure 4.6 Process map for United Arab Emirates 77

Figure 4.7 Process map for Yemen 78

Figure 4.8 Number of approved products by the five regulatory authorities (2008-2010) 83

Figure 4.9 Median approval times for all products (2008-2010) 84

XVII

Figure 4.10 Median approval time for Gulf companies products (2008-2010) 86

Figure 4.11 Median approval time for Arab non-Gulf companies products from

(2008-2010)

87

Figure 4.12 Median approval time for International companies‟ products

(2008-2010)

88

Figure 4.13 Median approval time for Asian companies‟ products (2008-2010) 89

Figure 5.1 Process map for GCC centralised registration 100

Figure 5.2 Total number of pharmaceutical products approved in the Gulf

Centralised Procedure (2006-2010)

102

Figure 5.3 Number of EASs approved in the Gulf Centralised Procedure (2006-2010) 105

Figure 5.4 Number of NASs approved in the Gulf Centralised Procedure

(2006-2010)

106

Figure 5.5 Approved pharmaceutical products (EASs & NASs) from GCC

international, Arab non-GCC and Asian companies (2006-2010)

106

Figure 5.6 Median approval time for all pharmaceutical products in the Gulf

Centralised Procedure (2006-2010)

107

Figure 5.7 Median approval time for EASs in the Gulf Centralised Procedure

(2006-2010)

108

Figure 5.8 Median approval time for NASs in the Gulf Centralised Procedure (2006-

2010)

110

Figure 5.9 Median approval time for different dosage forms for EASs and NASs in the

Gulf Centralised Procedure (2006-2010)

110

Figure 5.10 Median approval time for different therapeutic class for EASs and NASs in

the Gulf Centralised Procedure (2006-2010)

112

Figure 6.1 An evaluation of the Gulf states views and experience with Assessment of

GCC Central registration process (Instrument assessment)

122

Figure 6.2 An evaluation of the Gulf states views and experience with Assessment of

GCC Central registration process (Questionnaire)

123

Figure 6.3 The products which could potentially be registered under the Centralised

Procedure

131

Figure 6.4 Proposed approval timeline for products in Centralised procedure 132

Figure 6.5 Responses for the GCC authorities with regard to improving the GCC

Centralised Procedure

133

Figure 6.6 Member states assessment of the Centralised Procedure 135

Figure 6.7 Level of interaction between GCC-DR Secretariat and the Committee 136

Figure 6.8 Number of GMP Inspections conducted by GCC (2008 - 2010) 137

Figure 6.9 Number of Products evaluated by Oman, Qatar and Saudi Arabia (2008 -

2010)

138

Figure 6.10 Factors that affect the sustainability of the Centralised Procedure 140

Figure 6.11 The value of professional functions to the GCC-DR system by the Gulf

States

142

Figure 6.12 A comparison between the centralised and the national systems 145

Figure 7.1 An evaluation of the Pharmaceutical Companies experience with GCC

Central registration process (Instrument assessment)

157

XVIII

Figure 7.2

An evaluation of the Pharmaceutical Companies experience with GCC

Central registration process (Questionnaire)

159

Figure 7.3 Number of companies and their preferred pharmaceutical registration

system

165

Figure 7.4 Reasons for companies preference in using the Centralised

Procedure for product registration

166

Figure 7.5 Reasons why companies did not prefer the Centralised Procedure 167

Figure 7.6 Number of products submitted and approved through the Centralised

Procedure

168

Figure 7.7 The quality of decision-making of the Centralised Procedure 169

Figure 7.8 Companies‟ suggestions on how certain aspects of the registration

procedure could be simplified

170

Figure 7.9 Companies‟ view on the Centralised Procedure guidelines 172

Figure 7.10 Companies‟ views on the quality of the GCC-DR scientific advice,

efficiency and effectiveness of the centralised pharmacovigilance

procedures and the transparency of the Centralised Procedure

172

Figure 7.11 Companies‟ view of the level of interaction on the quality of information

received, timing of the registration procedure and their relationship with the

Registration Department of the GCC-DR

175

Figure 7.12 Companies‟ views on some of the ways to improve the relationship between

the companies and the GCC-DR

176

Figure 7.13 A comparison of the companies‟ views of the national versus the centralised

system with respect to scientific opinion and consistency of evaluations

179

Figure 7.14 Companies‟ views as to why a standardised pricing is not appropriate 179

Figure 7.15 Summary of responses on the questionnaire 182

Figure 8.1 Key issues to be consider in the new proposed GCC model 196

Figure 8.2 The Current GCC-CP registration system 199

Figure 8.3

Figure8.18

The proposed model for GCC-CP 200

XIX

LIST OF TABLES

Table 1.1 The demographic structure of the gulf cooperation council (GCC) states 11

Table 1.2 The structure, responsibilities and scope of activities within each of the

seven GCC regulatory authorities

12

Table 2.1 Data source for the seven Gulf authorities 26

Table 2.2 Features of consensus methods

29

Table 4.1 Models of assessment and characteristics in the Gulf States

79

Table 4.2 Number of approved products for Gulf Cooperation Council

(GCC) States in 2008, 2009 and 2010

82

Table 5.1 Number of EASs Approved in the Gulf Centralised Procedure from various

regions, dosage forms and therapeutic classes

103

Table 5.2 Number of NASs Approved in the Gulf Centralised Procedure from various

regions, dosage forms and therapeutic classes

104

Table 6.1 List of the seven participating authorities in the Gulf Cooperation Council

(GCC) States

130

Table 6.2 Number of internal and external personnel in different areas of expertise

within the Gulf States

141

Table 6.3 Relationships between capacity and workload for each Gulf State

(2008, 2009 & 2010)

142

Table 6.4 Summary of the major advantages

146

Table 6.5 Summary of the major disadvantages

147

Table 7.1 Companies‟ opinion regarding regulatory expertise within the GCC-DR

178

Table 8.1 Registration fees in the GCC States 208

1

CHAPTER 1

General Introduction

2

BACKGROUND

Modern medicines regulations are the foundation of any country‟s drug policy. This ensures a

viable pharmaceutical industry as well as a high standard for the drug approval process.

Throughout history, governments have regulated food and drug products and in general, the

focus of this regulation has been safeguarding the quality, safety and efficacy of these

products. Drug regulation is almost universal in the industrialised nations of the world and is

being progressively developed in third world countries. It is increasingly based on the

hypothesis that regulation is needed to ensure that new medicines will be comparatively safe

and effective, labelled accurately and marketed responsibly. In short, potential benefits and

harms of modern medicines are too important to be left to the market place and the

unregulated functioning of the pharmaceutical industry (Philip et al 1986).

Today, pharmaceutical products are highly regulated in most countries and need to comply

with strict legislative requirements before being authorised for sale. Therefore, individual

pharmaceutical regulatory bodies in each country are responsible for ensuring the safety and

effectiveness of human and veterinary medicines in their jurisdiction, in compliance with

local pharmaceutical legislation.

Regulatory Reviews Process, Approval Times and Patients' Access to

Medicines

Anderson (2004) commented on the importance of timeliness for national regulatory

authorities in order to approve new medicines, which may influence directly the stakeholders

and patients during the process. A lengthy approval process results in a delay in marketing

new approved medicines for patients. Normally, the length of the review process depends on

the type of products being registered, the requirements of the approval process and the type of

review carried out.

Governments are obligated to provide their citizens with access to new medicines and

therapies when they are needed. In other words, conducting safety and efficacy reviews of

marketing authorisation applications for new medicines and biotherapy products in a timely

manner should be a major priority for safeguarding and enhancing public health, which is

part of the core mission of health authorities. However, expediting the review process for new

3

medicines and biological products to ensure it is completed within predefined deadlines

should never mean that regulatory standards can be compromised as they are essential to

proving the safety, efficacy and quality of new medicines.

During the process of review and approval of new applications, the most important hurdles to

the pharmaceutical industry is the length of the review time (CMR, 2001). Therefore, efforts

have been made by several national authorities to allow patients‟ access to medicinal

products in a timely manner by reviewing their strategies to monitor the efficiency of the

review process, as well as the performance of the regulatory authorities (Mallia-Milanes,

2010).

Hill and Johnson (2004) suggested that in order to exploit the differences in registration

requirements of different countries for manufacturers they should synchronize and streamline

the registration process. Ultimately these unifying processes reduce the time lag for

registering new products, as well as reinforcing the 'assurance of quality' of medicines.

Furthermore, it is possible to complete and monitor the whole review process transparently

within a reasonable time frame satisfying both the manufacturers and regulatory authorities.

An effective review process is perceived through the overall approval times from submission

to patients‟ access to new medicines (Rawson, 2000; Anderson, 2004).

Many countries have legislated maximum times allowed for the review of dossiers. For

example, the target time-frame for completing the review process in the European Union

centralised system is 210 days. This authorisation period has two points known as „clock-

stops‟- at 120th

day and 180th

day. A time-scale of three months and one month, respectively,

will now be mandated for applicants to respond and these periods may be doubled upon

request (EMA, 2009). The longest review time usually occurs when the benefits of the

product are not evident.

A study reported by the Centre for Innovation in Regulatory Science (CIRS, 2013) on New

Active Substances (NASs) approved in the emerging markets between 2007 and 2011

indicated that there were considerable differences among countries in the time taken to

review medicinal products with median approval times ranging from one to three years

(Figure1.1 ).

4

Figure 1.1 Regulatory approval times from date of submission to date of approval

for New Active Substances (NASs) approved 2007-2011

Data are shown for NASs that were approved between 01/01/2007 and 31/12/2011. (n1) = number of drug applications, (n2)

= number of companies providing data. Box: 25th and 75th percentiles. Whiskers 5th and 95th percentiles =median

These study data (CIRS, 2013) for the median times for patients‟ access to NASs approved

by the three major drug regulatory authorities namely, FDA, PMDA, and EMA from 2003 to

2012 showed that the median time for patients access achieved by the US FDA was the

shortest among these three authorities (Figures 1.2 and 1.3).

Figure.1.2.Number of NASs approved by ICH agencies (EMA, FDA, PMDA)

by approval year (2003-2012)

5

Figure.1.3. Median approval time of NASs approved by ICH agencies (2003-2012)

Quality of the Review Process

It is a recognised fact that the efficiency of the drug regulatory review process does not

depend only on the speed of the review. In reality, the effectiveness of the regulatory process

should be measured in terms of the approval time and the quality of decision-making. Both

pharmaceutical companies and patients require a rapid registration process, but they should

understand that this must not be at the expense of the quality of the review (Jefferys,

1997;Lumpkin, 2000).

In the case of new drug applications (Lumpkin, 2000) the quality of the review depends

mainly on (i) the competence, consistency and experience of the reviewer and (ii) the

scientific soundness in communication, transparency, consistency and adequacy of the

process and feedback to the industry. Ultimately, the regulatory authority‟s primary

responsibility to the public is to expedite the availability of safe and effective new therapies,

however, pressure is also exerted on the authorities to constantly improve the efficiency and

quality of their review processes. On the other hand, dossier quality, as well as the robustness

and quality of the data submitted, are critical factors for achieving successful registration and

expediting market access (McAuslane et al, 2004). Furthermore, companies and regulatory

authorities have established open and frequent dialogue as regulatory factors that may

6

invariably result in enhancing the review process and review time (Cocchetto et al, 2000).

Normally, the drug review process (Jefferys, 1997) depends on the following parameters:

The review input: In order to ensure the availability of safe and effective medicines in the

market, governments usually have both legal requirements and guidelines. The assessment of

quality involves identifying and defining the role of legal requirements and how they can be

uniformly met with consistency. The clarity of information and communication between the

regulatory agency and the pharmaceutical companies about the expected quality will

influence the efficiency of the review process.

Clarity of roles: The credibility of the review process depends largely on the experts

involved although conflicts of interest undermine the process. The scientific review must be

independent of conflicts with suppliers of technology and they must also be protected from

political influence. An independent scientific review process will hold both suppliers and

purchasers accountable for decisions in the light of the scientific data.

Quality of data: Setting high standards of evidence are essential to the integrity of the drug

review process. However, it is often uncertain whether all of the data from the available trials

are being provided for the review. Requiring public registration of clinical trials and protocols

will enable agencies to know which findings are not being reported by manufacturers.

The scientific assessment: It is the responsibility of the reviewing personnel to establish the

consistency of the review and to maintain the quality and rigour of the scientific analysis. The

scientific basis on which a decision is made must be underpinned on up to date scientific

knowledge, procedures and expertise.

Transparency of rationale: Accountability in drug coverage decision-making requires that

all stakeholders understand the reasons for decisions. One of the major obstacles to such

transparency is currently the commercial confidentiality imposed by manufacturers (Morgan

et al 2006).

The output: The review process should help to ensure greater accountability of both

decision-makers and manufacturers by requiring full disclosure of all reasonable evidence

relevant to a medicine‟s potential coverage. The final decision and its communication to the

7

pharmaceutical company generally and the wider public must be rational, well-documented,

well-organised and transparent (Lumpkin, 2000). The quality of the review (Moss, 2004) will

finally depend on the methodical assessment of the reviewers and the reliable evidence

embedded in the data.

Benefit-risk assessment and Decision-making

Benefit-risk assessment is the basis of any regulatory authority‟s decisions in the pre-market

and post-market review process (EMA, 2012). A framework for medicines' benefit-risk

decision-making that summarises the relevant facts, uncertainties, and key areas of judgment,

clearly explains how these factors influence a regulatory decision and can greatly inform and

clarify the regulatory discussion. A universal eight step framework has been developed for

the Benefit-Risk assessment of medicines (Figure 1.4). This consists of the decision context

(step one), building the value tree (step two), refining the value tree (step three), assessing the

relative importance of Benefits and Risks (step four), evaluating the options (step five),

evaluating uncertainty (step six), a concise presentation and visualisation of results (step

seven) and expert judgment and communication (step eight). Such a framework can provide

transparency regarding the basis of conflicting recommendations made by different agencies

using the same information. Benefits and risks or harms assessment provide a summary of the

submitted evidence regarding the drug under review (Coplan et al, 2011). Key considerations

of benefits include the results of the pivotal clinical trials as well as appropriate analyses of

subpopulations for efficacy. Also the key considerations of risks include the robustness of the

safety database, the severity and reversibility of adverse events, and the sub-optimal

management of the post-market surveillance studies. In assessing benefits and risks,

consideration is also given to some factors that may be significant for a particular drug

review, including nonclinical pharmacology and toxicology data, pharmacodynamics and

pharmacokinetics, chemistry, manufacturing and controls and clinical microbiology. Risk

Management or ideally benefit risk management provides a summary and assessment of any

efforts that could help to lessen the identified safety concerns, or in other words ensure that

the medicine is prescribe for those patients for whom the risk or harm is considered

acceptable in the light of the benefits. Measures to reform the drug approval process have

focused increasingly on the decision bias that minimises unsafe or ineffective medicines but

neglects the costs of denying safe and effective drugs.

8

Figure 1.4 The Eight Step of the Benefit Risk Framework

Role of harmonisation

Harmonisation involves the formation of effective networks between regulatory authorities

(nationally, regionally and internationally) to facilitate the sharing of best practices, making

the best use of scarce resources and eliminating duplication of effort. Such networks are an

important element in building regulatory capacity and trust between different regulatory

systems (WHO, 2008). In recent years, considerable efforts have been made to harmonise

regulatory requirements in terms of scientific content and presentation of data in the

registration dossier, across various regions and countries. The meaning of „harmonisation‟ in

terms of the regulatory point of view is the standardisation of technical requirements for

medicines regulation. The policies of global standardisation (Trouiller, 2002) of regulatory

requirements have been set up, with the most notable example being the initiation of the

International Conference on Harmonisation of Technical Requirements for Registration of

Pharmaceuticals for Human Use (ICH). This initiative has disseminated a common set of

technical requirements relating to quality control (validation of procedures), drug safety and

efficacy as well as certain aspects of manufacturing practice for active ingredients.

Since medicines are essential to healthcare they should be available to the population of every

country. Medicines regulations remain an important component of promotion and protection

Framing the

decision

Step 1: Decision Context

Step 2: Building the Value Tree

Identifying benefits and risks

Step 3: Refining the Value Tree

Step 4: Relative

Importance of Benefit and

Risks

Step 5: Evaluating the

Options

Step 6: Evaluating Uncertaint

y

Step 7: Concise Presentation of Results Visualisation

Step 8: Expert

Judgement and Communication

Interpretation and recommendations

9

of public health because they help to ensure that patients have access to high quality, safe,

and effective medicines. Investing in the regulatory harmonisation initiative provides an

opportunity for strengthening regulatory capacity and the cost-effective use of limited

financial and human resources. Today regulatory authorities are thinking in terms of

regionalisation (Molzon.2010, 2011) through the efforts made by the International

Conference on Harmonisation.

The Global Cooperation Group (GCG) now includes the European Medicine Agency

(EMA), the African Regulatory Harmonisation Initiative (AMRH), the United States FDA,

the Association of Southeast Asian Nations (ASEAN), the Pan American Network for Drug

Regulatory Harmonisation (PANDRH), the Asia Pacific Economic Cooperation (APEC),

Southern African Development Community (SADC) and Japan. The Mercado Comundel Sur

(MERCOSUR) is the South American “Common Market” consisting of Brazil, Bolivia,

Argentina, Chile, Paraguay and Uruguay. This organisation is highly structured among the

Central and South American trade groups for regulatory harmonisation of pharmaceuticals

(Marcelo et al, 1998).

The structures of medicines regulation that exist today which include the drug laws, drug

regulatory agencies, the drug evaluation boards, quality control (QC) laboratories, drug

information centres, have evolved over time. Regulation of medicines encompasses a variety

of functions including licensing, inspection of manufacturing facilities and distribution

channels, product assessment and registration, adverse drug reactions (ADR) monitoring,

laboratory testing for the quality control of promotion and advertising and control of clinical

trials (Sauwakon et al, 2002). Each of these functions target a different aspect of

pharmaceutical activity and act in concert for effective consumer protection.

The Gulf Cooperation Council (GCC) States

The Gulf Cooperation Council (GCC) was established by an agreement concluded on the 25

th

May 1981 in Abu Dhabi (UAE) among Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and

UAE in view of their special relationship, geographic proximity, similar political systems

based on Islamic beliefs, joint destiny and common objectives (Figure 1.5). The GCC States

are located in the Arabian Peninsula southwest of Asia, bordered by Iraq and Jordan in the

North, the Republic of Yemen and the Arabian Sea in the South, the Arabian Gulf in the East,

11

and the Red Sea in the West. The total population of the six member states is 44,223,488

inhabitants in a total area of 2,572,954 square kilometres. Yemen is currently in negotiations

for GCC membership and hopes to join by 2016. The GCC has already approved Yemen‟s

accession to some areas such as the GCC Council of Health Ministers and the GCC Council

of Labour and Social Affairs Ministers. The demographic characteristics of the GCC are

shown in the table 1.1.

Figure 1.5 Map of the Seven Gulf Cooperation Council (GCC) States

GCC Drug Regulatory Authorities

The GCC authorities official names are as follows, Bahrain National Health Regulatory

Authority; Kuwait Drug and Food Control; The Directorate General of Pharmaceutical

Affairs & Drug Control Oman; The Pharmacy & Drug Control Department Qatar, Saudi

Food & Drug Authority; The Registration & Drug Control Department UAE; and the

Supreme Board of Drugs & Medical Appliances Yemen. These seven authorities form the

membership of the GCC Centralised Procedure system (GCC-CP). Five authorities are under

their respective Health Ministries and fully funded by their respective governments. Saudi

Arabia and Yemen, however, are independent stand-alone authorities that rely on registration

fees as the major source of their funding.

11

Table 1.1 The demographic structure of the Gulf Cooperation Council (GCC) States

Ref. The Cooperation Council for the Arab States of Gulf Secretariat General, Statistical Bulletin, Information Sector, Statistical

Department (Volume Twenty, 2012).

The seven GCC authorities regulate pharmaceutical products for human use with their main

activities such as marketing authorisation, post-marketing surveillance and quality control of

pharmaceutical and health products (Al-Essa, 2011). They also have a variety of other

responsibilities depending on the size and resources available for each regulatory authority

(Table 1.2).

Evolution of GCC-DR

The harmonisation of regulatory processes in the GCC States was initiated following the

consent of the GCC Health Ministers‟ Council Decree No. 8 in 1976 regarding the formation

of a study group to report on how a centralised registration system should be set up to

monitor medicines and establish common guidelines for the participating authorities (Hashan,

2005). In 1997, the State of Bahrain submitted a proposal for the formation of a Central

Committee of Gulf States to register pharmaceutical companies and their products to ensure

basic standards for the manufacture of good quality medicines and also to unify the

regulations relating to export of medicines from the Council States.

Country Area / sq

Km

Population Median

age (years)

Life expectancy

at birth (years)

GDP ($) GDP per

capita ($)

Bahrain 760 1,234,571 30.4 75.4 28.27 billion 17763

Kuwait 17,818 2,672,926 26.4 77.89 137.7 billion 46509

Oman 309,500 2,773,479 23.9 73.97 72.78 billion 21355

Qatar 11,586 1,715,010 30.8 75.51 100.8 billion 74839

Saudi

Arabia

2,149,690 27,563,432 24.9 73.87 590.9 billion 16355

UAE 83,600 8,264,070 30.2 76.32 191.9 billion 36017

Yemen 527,968 23,495,361 17.9 63.36 57.95billion 2,500

Total 3,100,922 67,718,849 - - - -

Average - - 26.4 73.76 168.47 30,762.57

12

Table 1.2 The structure, responsibilities and scope of activities within each of the seven GCC regulatory authorities*

*Adopted from Al-Essa, 2011

Country Bahrain Kuwait Oman Qatar Saudi Arabia UAE Yemen

Name of Authority National Health

Regulatory

Authority

Kuwait Drug and

Food Control

The Directorate

General of

Pharmaceutical

Affairs & Drug

Control

The Pharmacy &

Drug Control

Department

Saudi Food &

Drug Authority

The Registration

& Drug Control

Department

Supreme Board of

Drugs & Medical

Appliances

Independent stand-alone authority X X X X √ X √

Budget / GBP NA 2million NA NA 85million 1.6million 2million

Fees / GBP 9 230 130 None >5000 NA 470

Scope of

registration

responsibilities

Medicines for

human use

√ √ √ √ √ √ √

Veterinary

medicines

X √ X X √ √ √

Medical devices

and in-vitro

diagnostics

√ √ √ √ √ √ X

Cosmetic

products

X √ X X X X X

Food

supplements

X √ X X X X X

Herbal medicines X √ X X X X X

Scope of

activities

Marketing

authorisation

√ √ √ √ √ √ √

Post-marketing

surveillance

√ √ √ √ √ √ √

Sample analysis √ √ √ √ √ √ √

Advertising

control

X √ √ X √ √ X

Price regulation √ √ √ √ √ √ √

GMP inspection √ √ X √ X X

Clinical trial

authorisation

√ X X X √ √ X

13

The Gulf Central Committee for Drug Registration (GCC-DR) was formed in May 1999 and

includes Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, UAE, and Yemen. The GCC Drug

Registration Committee, composed of two members from each of the seven countries, advanced

in three stages. In September 2005, an intra-GCC Free Trade Area Agreement, came into effect

by which all GCC national products including pharmaceuticals were exempted from custom

duties within the GCC and any single consignment of foreign goods were charged import duty

only at the port of entry into the GCC area. The formation of effective networks among national

regulatory authorities participating in various harmonisation initiatives has several advantages. It

facilitates the sharing of limited resources; eliminates duplication of activities; saves capital

expenditure for all; supports cooperation and collaboration and international understanding;

facilitates the building of an efficient regulatory capacity; and enhances public trust in the

regulatory efforts (Jamel, 1998). The first stage of this initiative was a two year period during

which all pharmaceutical and research-based companies in the Gulf region were registered; in

the second stage the GCC-DR systems were evaluated and generic medicines from local

manufacturers registered and the third stage involved the appraisal and registration of all

complementary pharmaceutical products such as cosmetics and herbal compounds.

The Ministers of Health in 1999 agreed the two-phase proposal submitted by the Executive

Office of the GCC Ministers of Health for Central Registry and approved the registry

regulations. During phase one (1999-2001) new pharmaceutical products were assigned to

register with both the local authority and the new Central Registration authority and included the

registration of pharmaceutical companies. This also applied to new chemical entities and

biological products. Phase two of this process started in 2002, mainly targeted to assess the

whole system of the registration process and the inspection of pharmaceutical manufacturing

plants. In fact, it was recognised that if the knowledge and experience of different authorities are

shared for a specific task or responsibility, the best practice from each system could be combined

for the advantage of all member states.

Since the GCC States constitute one regional community in its religion, language, population,

similarity in geography, values, history, traditions, economic resources, social and cultural

circumstances, they had to unify their efforts in different fields of life to face the rapid changes

and the overall development requirements. The procurement of safe and effective pharmaceutical

14

products, hospital sundries and equipment of high quality at appropriate prices are organised

through a central group purchasing program. Furthermore, the mission of GCC–DR is to

establish a unified Gulf Drug Registration System that ensures effectiveness, safety and quality

of medications as well as good manufacturing practices (GMP) according to international

standards and post marketing surveillance after registration. The GCC-DR also emphasizes the

use of highly effective and safe medications to protect public health in the Gulf Countries. The

government control over medicines has grown in the last hundred years and now

pharmaceuticals are among the most-regulated products in the world. At present, about 20% of

countries have fully operational medicines regulations, 30% have either none or very limited

drug regulation and a few have regulations of varying capacity (WHO 2006). In reality, many

developing countries cannot ensure the safety, efficacy and quality of medicines available in

their markets because they are resource constrained in terms of staffing, standard systems and

training (WHO, 2008). However, the globalisation of pharmaceutical markets and production has

also increased the spread and prevalence of unsafe medicines.

Protection of public health is the primary aim of any drug regulatory authority and is the

foundation of any country‟s national drug policy that ensures a viable pharmaceutical industry as

well as a high standard drug approval process. However, regulation is perceived as an obstacle

to the availability of medicines in national or regional markets and has placed a significant

demand on regulators to accelerate reviews and evaluations to approve new medicines in the

shortest possible time (Hill, 2004)

The study by Hashan (2005) emphasized the differences between authorities in the GCC States in

the areas which include structures, procedures, available resources, measures of quality &

performance, degree of harmonisation within and between processes and approval times. The

study provided a comprehensive understanding of the medicine regulatory processes in the Gulf

States. It also elaborated the need for greater standardisation in requirements, performance,

procedures and guidelines in the Gulf and other Arab countries which may lead to one regulatory

body in the Gulf region.

The study by Al-Essa (2011) demonstrated the added value of the a harmonised strategic

planning process in the GCC region. This research explored the differences in the Gulf States

15

which included structures, procedures, resources, quality measures and strategic parameters

which facilitate an effective drug approval process for pharmaceutical companies in the GCC

region.

The quality of the review in the GCC

The regulatory review process consists of the scientific evaluation of all data generated during

product development which are described in the registration dossier and when data are

considered satisfactory a marketing approval is granted. The key advantage of the centralised

system in the Gulf is the availability of external expertise to complement the internal evaluators.

This enhances the quality of the reports and more information is focused on the registration to

ensure that product evaluation is carried out according to the required standards. In this manner,

the quality of the product registration is assured across the GCC States.

Apart from obtaining an improved scientific evaluation from more than one state following an

evaluation of the application dossiers, the CP allows further scope for the exchange of

knowledge, ideas and experiences among the National Drug Regulatory Authorities in the GCC.

This results in better coordination and quality reviews within the GCC.

The scientific evidence developed by a pharmaceutical company is evaluated to ensure that the

product can be made available for use or prescribed to patients. Regulators must balance between

the speed of access of the medicine to patients and ensuring that its benefits outweigh any risks.

According to Dureja el al (2010) a well-funded, consistent, robust and transparent regulatory

review system is indispensable to protect the public health and build confidence in the marketed

medicines. Gradual strengthening of the regulatory authorities in the GCC region is fundamental

so that they have the expertise and tools for evaluating new medicines efficiently. Also it is very

important to analyse and scrutinise the differences and uniformity among the regulatory review

processes carried out in all the GCC authorities.

Mallia-Milanes et al (2010) reported on the influence of the type of assessment carried out by

different authorities which may affect the regulatory approval times. The study pointed out the

existence of three types of review process offered for pharmaceuticals in Singapore which

includes full, abridged and verification reviews.

16

A full review relates to products that have not yet received approval elsewhere and takes around

270 working days in Singapore to be completed and supported by external reviewers. The

abridged review usually takes 180 working days, which is used for applications that have been

approved by a recognized regulatory authority, (eg. US FDA, EMA, TGA, etc), before

submission in Singapore. The verification review can be effected if the medicine has been

approved by at least two benchmark authorities and takes a minimum of 120 working days.

McAuslane and Walker (2007) reported in a study of ten agencies, that Argentina alone utilizes

the verification review system for pharmaceuticals and biologicals while Mexico, Egypt, Saudi

Arabia, Malaysia and Singapore make use of the abridged assessment for most of their

applications. Walker et al., (2005a, 2005b and 2005c) stressed the significance of the pattern of

the review process carried out by the regulatory authorities for pharmaceuticals in a timely

manner.

The primary issue to be addressed is the understanding of the type of model being used to carry

out dossier assessment in each GCC country and to quantify the extent of the scientific review

approved in each member state. Karlton et al (1997) pointed out the importance of the quality of

the dossiers in the realisation of rapid regulatory reviews and approval of new applications.

Mediocre documents complicate the review process and may impact negatively upon the

confidence in quality of the medicinal product and its manufacturer (Zellerhoff, 2001). It is the

duty of the manufacturing companies to submit high quality dossiers for improving the

efficiency of the approval process. Valuable capacity development and an effective application

tracking system, assessment and decision-making, appropriate use of information technology,

effective working, accountability and transparency of the medicine registration related decisions

finally result in the overall competence of a unified registration process.

Global drug development and its influence on the regulatory environment in

the Gulf Region

The World Trade Organisation (WTO) established a global patent protection act named TRIPS

(Trade-Related Aspects of Intellectual Property Rights) (WHO, 2003a) in regards to New

Chemical Entities (NCEs) in 1994. Patents can relate directly to active ingredients, formulations,

17

pharmaceutical salts, isomers, polymorphs, combinations, manufacturing processes and also the

patent holder has the complete freedom to set the price. The seven Gulf States, with the

exception of Yemen, recognised the TRIPS agreements. However, the TRIPS agreement

eventually results in a price increase for new medicinal products which is unaffordable to most

people living in developing countries (WHO, 1999,2004).

The world pharmaceutical market in 2014 is estimated to be around one thousand billon US$.

The Middle East and North Africa (MENA) in 2007 comprise around 2% of the global

pharmaceutical market, with an average annual growth of 10.4%, the Arab market (22 Arab

countries) comprises 1.5%, valued at around US$6.2 billion, of which the largest market is the

Saudi Arabia, valued at around US$1.2 billion (Veronica, 2011; Nixon et al, 2013). The

increasing number of conferences and studies on the central drug registration process reflects the

need for greater harmonisation in medicine regulation within the Middle East and it is with this

background that this research was initiated.

18

AIM AND OBJECTIVES OF THE STUDY

Aim

The aim of this study is to evaluate the GCC centralised procedure and the approval times since

it inception in 1999 to 2010.

Objectives

Evaluate the regulatory review process in Oman and identify the milestones and timelines

(2006-2010)

Identify the strengths and weaknesses of the Oman regulatory review process and propose

strategies for improvement.

Determine the similarities and differences in the regulatory reviews in each of the seven GCC

states together with the characteristics of the review process.

Examine the trends in the submission, registration and the associated approval timelines for

patients‟ access to medicines in the GCC states.

Appraise the GCC central registration regulatory review process.

Examine the views and experiences of the GCC states and the pharmaceutical companies

with respect to the GCC registration procedure.

Identify the strengths and weaknesses of the centralised review process and propose

strategies for improvement

Develop a new model for the GCC-DR based on the evaluation and outcome of the

centralised procedure since its inception.

19

CHAPTER 2

Study Rationale and Methodological

framework

21

RATIONALE OF THE STUDY

The decision to centralise Drug registration within the GCC was a political one. Many were

skeptical as to whether such centralisation would improve the time line in registering new

medicines and thus facilitate earlier availability of new drugs to the population. Furthermore,

individual countries were experienced in registration processes and believed that they were

efficient enough. A number of such officials indicated that the individual countries were being

deprived of their sovereignty and equality, they were therefore skeptical about the success of

such initiative. Pharmaceutical companies were also doubtful about the GCC-DR system as to

whether it would improve the review process and the approval timelines in the GCC region.

Many countries had adopted joint drug registration procedures and it is assumed that the process

works and delivers efficiency. As it is now more than 10 years (1999) since the centralised drug

registration system was established in the GCC, it was timely for an assessment of the GCC-DR

timelines and the number of registered products to be evaluated. In addition it was decided to

conduct a comparative study between the GCC-DR and the national approval timelines to

complete the picture for both the individual authorities and the pharmaceutical companies.

It is intended to conduct studies involving the major stakeholders in the registration process.

Current officials responsible for registration in the respective country, pharmaceutical

manufacturers and those within the GCC-DR secretariat will be requested to participate in these

studies. The questionnaire technique will be used for data collection to determine the success and

impediment to the intended progress of the GCC-DR.

In the light of the GCC Central Drug Registration system, the seven regulatory authorities have

had a long experience in joining their efforts to centrally register pharmaceutical products in the

Gulf region. They were apprehensive about the possibility of changing their entire procedures

and practices.

These concerns led to the conceptualisation of this study in order to examine the views of the

seven GCC authorities about the current status of the GCC-DR system and its impact on their

individual processes. Also the current research has focused on evaluating the pharmaceutical

21

industry‟s views about the advantages and disadvantages of the GCC-DR system and how this

has impacted the speed of marketing authorisation for their products in each Gulf State.

METHODOLOGICAL FRAMEWORK

Development of the Study design

The present study employs the principles of quantitative, exploratory and constructive research

methodologies with the primary aim of evaluating the GCC central drug registration procedure.

Background and review of the Study design

The Quantitative data collection methods rely on random sampling and structured data collection

instruments that fit diverse experiences into programmed response categories. These methods

produce results that are easy to summarise, compare, and generalise. Depending on the research

questions, participants may be randomly assigned to different treatments and data collected on

participants relevant to the outcome being measured. (Kidder et al,1987).

A cross sectional design will be adopted for data collection to gather specific data pertaining to

all the seven Gulf States at different phases of the study. There are several advantages of the

cross-sectional design, such as requiring less resources and being able to collect a large volume

of data in the shortest possible time. The questionnaires, as assessment tools are important

aspects of any research of such nature and usually reflect the perception of individual members

of the target population about a particular issue. Furthermore, questionnaires techniques are used

in studies to elicit reports of facts, attitudes, and other subjective states. A questionnaire is

usually composed of a set of questions, answered by potential clients or the target population.

The results can be presented as a table or a graph. A well-structured study using questionnaire

techniques includes a clear and comprehensive statement of the study goals, data requirements,

and the analysis plan (Dillman & Don et al, 1978; Bradburn et al, 1982).

Several different types of studies are utilized depending on the approach used and the overall

study objectives expected. A one-off data collection is selected for the present study which can

22

also impart the advantages of baseline and comparative assessment points (Salant et al, 1994;

Anon, 2000; Passmore et al, 2002).

Th e ma jo r s t reng th s and w ea kn ess e s o f questionnaire techniques are as follows:

S t reng th s

1. Are particularly useful in describing the characteristics of a large population.

2. Can be self-administered making it feasible to recruit large samples.

3. Are flexible and the least costly method of data collection.

4. Results can be generalised.

W eakn es s es

1. Often appear superficial in their coverage of complex topics.

2. There is no way of telling how much thought a respondent has put in to the responses.

3. There is no way to tell how truthful a respondent is being.

4. Lacks validity.

5. People may read differently into each question and therefore reply based on their own

interpretation of the question.

6. Questionnaires also invite people to lie and answer the questions very vaguely which they

would not do in an interview.

Data Collection

Development of Data Collection Techniques

In deicing an appropriate data collection technique for this study questionnaires were reviewed

alongside interviews. The cardinal difference between the two is that the questionnaires can

produce either quantitative or qualitative data whereas interviews produce qualitative data. The

attributes and different types of the two techniques are presented here.

Questionnaires

Questionnaires are usually an inexpensive and efficient method where no special conditions or

equipment are required. It can also be compiled anywhere and distributed easily and the

information can be collected from a large group of people in a timely manner. In a questionnaire

23

everyone answers the same questions therefore it can be compared easily. Learning how to

design and use structured interviews, questionnaires and observation instruments is an important

skill for researchers. Interviews have certain advantages over self-completion questionnaires.

The interviewer can explain questions that the respondent has not understood and can ask for

further elaboration of replies. However, interviews are more time consuming and it may also be

open to interviewer bias, where the interviewer influences the replies by revealing their own

opinions. Such biases can be avoided by using self-completion questionnaires.

Interviews

The interview is a more flexible form than the questionnaire technique and, if wisely used, can

generally be employed to gather information of greater depth and be more sensitive to contextual

variations in meaning. Interviews, however, can be non-scheduled, though still partly

standardised. This is sometimes called a semi-structured interview. Here, the interviewer works

from a list of topics (checklist) that need to be covered with each respondent, but the order and

exact wording of questions is not important. Generally, such interviews gather qualitative data,

although this can be coded into categories to be made amenable to statistical analysis.

The main advantages of the interview technique include (McNamara, 1999; Bourque and

Fielder, 2003a):

The presence of an interviewer allows for complex questions to be explained, if

necessary, to the interviewee.

Interviews can generally be longer than when self-completion techniques are used as

interviewees are less likely to be put off by the length or to give up halfway through.

There is more scope to ask open questions since respondents do not have to write in their

answer and the interviewer can pick up on non-verbal clues that indicate what is relevant

to the interviewees and how they are responding to different questions.

Visual aids can also be used in the face-to-face situation.

The major limitations of the face to face interview are discussed below.

The cost associated with face-to-face interviews can limit the size and geographical coverage of

the study. Interviewers can introduce bias, which will affect the reliability of responses. Such

bias might emerge from the way in which questions are asked, or in the personal characteristics

24

of the interviewer, or in respondents‟ wish to give socially desirable responses. For instance,

there tends to be an over-reporting of voting activity and of participation in voluntary activities

in data gathered through interviews.

The studies using self-completion questionnaires have some distinct advantages over face-to-

face interviews:

They are inexpensive to administer. The only costs are those associated with printing or

designing the questionnaires, their postage or electronic distribution.

They allow for a greater geographical coverage than face-to-face interviews without incurring

the additional costs of time and travel. Thus, they are particularly useful when carrying out

research with geographically dispersed populations. Using self-completion questionnaires

reduces biasing error caused by the characteristics of the interviewer and the variability in

interviewers‟ skills. The absence of an interviewer provides greater anonymity for the

respondent. When the topic of the research is sensitive or personal it can increase the reliability

of responses.

Telephone interviews

Telephone interviews using interview schedules are becoming increasingly efficient with

sophisticated developments in computer technology. Computer assisted telephone interviewing

(CATI) systems are available and these provide clear instructions for the interviewer, display the

interview schedule and allow electronic recording of responses as they are given. This omits the

data entry part of the research because responses are recorded directly onto the computer.

The major advantages associated with telephone interviews are as follows:

The researcher does not have to travel; interviews can take place over a wider

geographical area.

There are fewer interviewer effects ie. The personal characteristics of the researcher will

be less obvious than in face-to face situations and is therefore less intrusive.

The physical safety of the interviewer is not an issue.

Telephone interviews are subject to greater levels of monitoring because supervisors can

unobtrusively listen in to interviews to ensure that they are carried out correctly

25

Different Types of Questionnaire Techniques Used in Data Collection

Several methods are available for collecting data using the questionnaire technique and also

depend on many factors for selecting the most appropriate method. These include the type and

size of population being studied, timelines, budget, resources and purpose of the study (Diem,

2002a).

Paper or electronic mail-delivered

This method utilizes minimum resources to prepare; enables privacy of responses and it is

relatively inexpensive or free of charge, still it may take time and requires follow-up to obtain

representative responses.

Group-administered

This approach involves gathering a group of responders together administering the

questionnaires and asking the group to complete them individually.

The method ensures a high response rate from those who receive the questionnaire and enables a

full explanation of the study with the opportunity for questioning. The disadvantages of this

method are the limited time availability for the responders to formulate their answers and the

slow turnaround time. (Trochim, 2006).

Telephone-administered

This method utilizes pre-arranged telephone calls with the study participants and by recording

the calls; the investigator can generate a digital data base with the interview texts. The time

zones and languages among respondents may be a hurdle of this method leading to no contacts

(Diem, 2002a; Trochim, 2006). It may also be possible to utilize an automated system where the

study participants record their responses via a touch-tone telephone to a computer-based

interview system. Text messages, to remind the respondents, together with cell phone facility

may be utilised in this method.

Web-based method

In this method, the questionnaires may be displayed and posted on a web site which is to be

completed by respondents in a fixed time period remotely. Web-based methods enable a quick

and easy response and are inexpensive (Diem, 2002b; Bourque et al, 2003a ).

26

Data Source

Information will be sought from the seven regulatory authorities who are members of the Gulf

Cooperation Council (GCC) States (Table 2.1).

Table 2.1 Data source for the seven Gulf authorities

Inclusion Criteria

For the Oman study and the evaluation of the review process and timeline in the individual GCC

countries, all products from local, Gulf, Arab non-Gulf and international manufacturers, which

have been approved for human use between 2006 and 2010 and 2008-2010 respectively, will be

included. This includes: New Active Substances (NASs) and Existing Active Substances (EASs).

The products which have complete date information e.g. submission date, regulatory evaluation

time, companies‟ response time to the regulatory queries and approval dates will be included in

the total approval time. In the GCC Centralised Procedure and GCC States studies, all products

from local, Gulf, Arab not-Gulf and international manufacturers approved for human use

between 2008 and 2010 will be included.

Position Agency Country

Director, Pharmacy & Drug Control Ministry of Health Bahrain

Drug Registration and Release Superintendent Drug and Food Control -

Ministry of Health

Kuwait

Director General of Pharmaceutical Affairs &

Drug Control

Directorate General of

Pharmaceutical Affairs and

Drug Control- Ministry of

Health

Oman

Head of Drug Registration Section Drug Control Department-

Supreme Council of Health

Qatar

Executive Director of Licensing Department -

Drug Sector

Saudi Food and Drug

Authority

Kingdom of Saudi

Arabia (KSA)

Head of Registration and Pricing Department

Drug Control Department -

Ministry of Health

UAE

Member of the board council Supreme board of drugs and

medical appliances

Yemen

27

The opinions and suggestions of all the seven GCC states from the respective regulatory

authorities as well as the pharmaceutical companies on their experiences with GCC central

registration procedure will be collected by means of questionnaires.

Exclusion Criteria

Products which have incomplete data such as missing submission date or approval date will be

excluded from the final analysis.

Data Collection Procedure

Confidential procedures will be used for all parts of the study. All the collected data may be

aggregated to avoid identification of individual responders. The electronic or interviewer

delivered questionnaires will be used to collect data which may allow the confidentiality and/or

anonymity of the procedure ((Crow and Wiles, 2008). A questionnaire is useful when there is a

need to collect information from the study participants in a reasonable time period. It is a

structured technique for collecting primary data in a study using a series of structured questions

for which the respondent provides answers. (Diem, 2002b)

Data Collection Monitoring and Timeline

A face-to-face meeting will take place to follow-up the data to be obtained from the Oman drug

authority and to closely observe the regulatory review processes and the approval timelines in

Oman. In addition, a face-to-face meeting with all the Directors and General Directors of

Regulatory Affairs in the Ministry of Health in the GCC States will take place during the GCC-

DR committee meetings. All the participants will be asked to provide the registration data for

products approved in 2008, 2009 and 2010 based on the milestones in each authority.

Clarification (validation) regarding the data set will be obtained from the GCC authorities

through telephonic conferences and electronic mails.

The comparisons of the Gulf States and pharmaceutical companies' perspective on the

effectiveness of the GCC centralized procedure require telephone-interview and email delivered

questionnaire in order to:

Identify the similarities and differences between the experiences of regulatory authorities

and pharmaceutical companies with the Gulf Centralised Procedures

28

Provide recommendations to improve the Gulf Centralised Registration Procedure

Propose the strategies to maximise the benefits of a centralised registration system

Collect feedback about the GCC centralized procedure questionnaire from the GCC

regulatory authorities and pharmaceutical companies. Attempts will be made to clarify

areas of the questionnaire which maybe unclear to the participants

Development of Questionnaires

There are different types of self-completed questionnaires such as mail-delivered, web-based or

email-delivered. The email-delivered and web-based questionnaires will be adopted for this

study . Following a series of consultations with experts and key regulators, it will be possible to

test the applicability of the questions to evaluate views and experiences of the Gulf States with

respect to the Centralised Procedure by conducting a pilot study involving two randomly selected

GCC authorities.

Another questionnaire will be developed to evaluate the experiences and views of

pharmaceutical companies with respect to the central registration review process. A pilot study

will be conducted involving five pharmaceutical companies (two innovative and three generic) to

examine the practicality and applicability of the industry questionnaire.

Chapters three, four, five, six, seven and eight will aim to provide evidence to establish

consensus opinions on topics that do not have adequate information currently available. The

studies in these chapters will focus on the collection of both qualitative and quantitative

information. In situations where there is a need to define levels of agreement on controversial

subjects but there is no unanimity of opinion because little evidence exists or available evidence

is contradictory, consensus methods can be used. These methods attempt to assess the extent of

agreement (consensus measurement) and resolve disagreement (consensus development) (Jones

et al., 2000).

The most commonly used consensus methods are the Delphi process, the nominal group

technique (also known as the expert panel) and the consensus development conference. The aim

29

of consensus methods is to determine the extent to which experts agree about a given issue (Jones

et al., 1995). The features of consensus methods are described in table 2.2.

Table 2.2 Features of Consensus Methods (Jones and Hunter, 1995)

Anonymity To avoid dominance; achieved by use of a questionnaire in Delphi

and private ranking in nominal group

Iteration Processes occur in "rounds", allowing individuals to change their

opinions

Controlled feedback Showing the distribution of the group's response (indicating to each

individual their own previous response in Delphi)

Statistical group response Expressing judgement using summary measures of the full group

response, giving more information that just a consensus statement

Consensus Development Conference (CDC) method

Consensus Development Conference is a formal method developed by the US National Institutes

of Health in 1977, for gaining feedback facilitated through face-to-face contact. A key feature of

this method is the appointment of a carefully selected panel of people thought to be without

vested interest, to listen to the evidence presented at a CDC meeting and prepare a report on the

topic under discussion with recommendations (Fink et al, 1984).

Nominal Group Technique

The nominal group technique (NGT) is a group problem solving process involving problem

identification, solution generation and decision-making. The NGT is a structured method for

group brainstorming that encourages contributions from everyone.

This approach was developed in the USA in the 1960s which includes a highly structured

meeting organized to collect information from appropriate experts about a given topic or issue. It

involves two rounds in which panelists rate, discuss and then re-rate a series of items or

questions. This technique is most commonly used in healthcare to examine the appropriateness

of clinical interventions and has some features in common with focus groups (Jones et al, 2000).

This method focuses on a single goal, e.g. the definition of criteria to assess the appropriateness

31

of a gene therapy intervention, rather than eliciting a range of ideas and it will therefore not be

appropriate for the studies considered for this thesis.

Delphi approach

It is a forecasting method based on the results of questionnaires sent to a panel of experts.

Several rounds of questionnaires are sent out, and the anonymous responses are aggregated and

shared with the group after each round. The experts are allowed to adjust their answers in

subsequent rounds.

Because multiple rounds of questions are asked and each member of the panel is told what the

group thinks as a whole, the Delphi Method seeks to reach the "correct" response through

consensus. The Delphi technique was developed in the 1950s by RAND Corporation in Santa

Monica, California (a non-profit institution that helps improve policy and decision-making

through research and analysis) (Kaplan et al., 1950; Woudenberg, 1991). Since then the method

has been adopted and interpreted widely in health services research (Mead et al, 2001) to obtain

judgement from expert panels by systematically collecting and aggregating informed opinions

from a group on specific issues.

The Delphi method seeks to aggregate opinions from a diverse set of experts, and can be done

without having to bring everyone together for a physical meeting. This anonymity promotes a

sense of freedom to express opinions without negative repercussion (Annells et al, 2003). The

Panel members are encouraged to revise previous responses in subsequent iterations after

reviewing new information submitted by other experts.

The Delphi approach can be a quick, inexpensive and a relatively efficient way of combining the

knowledge and abilities of an expert group on a particular issue. It is viewed as a useful

communication tool for generating debate as opposed to reaching conclusions. For the purpose

of this study, the essence of the Delphi approach will be used to develop consensus of opinions

in each of the previously defined topic areas as well as to collect information that can be used as

scientific evidence (Figure 2.1). It is, therefore, imperative that detailed information be given

about the proposed method of data collection and if questionnaires are used, their development

should be described. Having defined the key problem in each of the research areas and identified

31

the appropriate individuals from regulatory authorities in the area, a pilot study will be conducted

in the first round. Comments from the experts will then be incorporated and used to refine the

questionnaire that will be mailed to all participants. Then the results from the questionnaire will

be aggregated and analyzed before being reported back to participants.

Figure 2.1 Adoption of the Delphi Approach to be used in this study (Mead et al., 2001)

Development of the Study Plan

A comprehensive review and critical analysis of the literature reported in chapter one,

demonstrated a significant gap in the area of the drug regulatory process for the Gulf countries

(i.e. Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, UAE and Yemen) and the GCC Centralised

Procedure. In order to close this gap and improve the regulatory performance, it is vital to

understand the regulatory review practices and evaluate the Gulf States and pharmaceutical

companies' views and experiences with GCC Centralised Procedure to achieve an effective and

improved Gulf Centralised regulatory system. Therefore, the following study plan was developed

to capture data on the regulatory environment in the Gulf. These were then subjected to a

significant scrutiny to fulfill the objectives of the study.

32

The research project will consist of six smaller studies each forming a thesis chapter that

explores the core concepts of GCC drug regulatory field, namely,

Evaluation of Oman Pharmaceutical Regulatory Review Process (Chapter three)

Evaluation of the Regulatory Review Times in the GCC States (Chapter four)

A comparative study of the centralised regulatory review processes in the seven

GCC States. (Chapter five)

An Evaluation of the Gulf States Views and Experiences with GCC Centralised

Procedure. (Chapter six)

An Evaluation of the Pharmaceutical Companies Experiences with the GCC

Centralised Procedure. (Chapter seven)

The Gulf Centralised Procedure- A Comparison between the Experiences of

Regulatory Authorities and Pharmaceutical Companies (Chapter eight)

The outcomes of the research will be combined to derive the major areas that require further

improvement to achieve a standardized and efficient regulatory review process for the GCC

centralised system. The following methods will be employed to collect the required data:

1. To obtain a list of the key regulatory personnel in each drug regulatory authority in the

GCC region.

2. A review of the literature and/publications on the subject of regulatory review process in

the GCC States their centralised system.

3. To consult with regulatory experts and senior managers in the GCC regulatory

authorities.

4. To develop two questionnaires with which to evaluate the Gulf States and pharmaceutical

companies' views and experiences with GCC Centralised Procedure.

5. To produce two reports as a result of the assessment of the GCC centralised regulatory

review process and the Comparison between the experiences of regulatory authorities and

pharmaceutical companies with the GCC Centralised Procedure.

6. The reports will form the basis of the relevant chapters in this thesis.

33

Development of the Study Instruments

The sequence of events to be carried out to achieve the aim of the study will start with an

evaluation of the regulatory approval timelines in Oman. This is a lengthy process which

involves collecting data on the registration dates for 2006, 2007, 2008, 2009 and 2010 from the

saved documents in the Oman MOH archives.

During the course of collecting data on the approval timelines in Oman, two questionnaires to

examine the views and experiences of the Gulf Cooperation Council states and pharmaceutical

companies, with respect to the Gulf central registration procedure will be prepared. The first

questionnaire is planned to be distributed among the seven regulatory authorities in the GCC

states and the second is intended for completion by pharmaceutical companies, already registered

or yet to register their products through GCC centralised registration procedure. A pilot study is

planned to be carried out by coordinating two GCC states and five pharmaceutical companies to

assess the practicality, feasibility, applicability and relevance of the study instrument for

assessing the Gulf Centralised Procedure.

The review times for New Active Substances (NASs) and Existing Active Substances (EASs)

submitted to the GCC Centralised Registration will be obtained directly from the Executive

Board of the Health Ministers Council for GCC States. Since the GCC registration office do not

maintain a robust and complete electronic system of data capture, the data collection will have to

be carried out manually.

Psychometric evaluation of the survey questionnaires

Evaluation process

Questionnaires should undergo evaluation of their psychometric properties before they are relied

on for making decisions. Psychometric validation is used in various fields including education,

psychology, and health research to define the properties of the scales which are included in such

questionnaires. Psychometric principles such as applicability and acceptability, validity,

reliability, consistency and responsiveness are considered in the present study (Mallia-Melanes,

2010).

34

Applicability and acceptability for use

Usually the applicability of a study instrument (Stewart, et al 1990) guarantees the

appropriateness of its content to the purpose of the research being conducted. Furthermore,

applicability describes the suitability of an instrument for its intended use in terms of wording,

clarity and simplicity of language (Higginson and Carr, 2001). The willingness to respond to the

questions by the study participants is another critical aspect in the acceptability of the study

instrument. It also considers the time required from the participants to complete the

questionnaire and whether the questions are clear, concise and easy to understand (McLeod et al,

2008).

Practicality

Practicality issues include the participant‟s comfort, cost and mode of administration of the study

instrument (e.g. interviews or self-administered), convenience and ease of understanding of the

questions (Ware et al, 1980a, 1981). The participants‟ lack of engagement can result in a low

response rate, and high refusal rate, missing responses and longer administration time.

Validity

According to Kaiser and Smith (2001) validity is the most fundamental consideration in

developing and evaluating tests. The most commonly used validity methods for assessing study

instrument are content (face) validity and criterion validity. The concept refers to the degree to

which evidence and theory support the interpretations of test scores demanded by proposed uses

of tests". Ultimately the concept of validity measures what the method claims to measure and

investigate sensitive issues of such method.

Content Validity

This method assesses the extent to which questions in a study serve to encompass the important

facets of the notion the indicator is supposed to represent in a balanced way. The weighting of

the results are also reviewed with the set of indicators (Anon, 2001).

Criterion Validity

The aim of the criterion validity is to correlate a new indicator with reference to a previously

well established indicator (Anon, 2001) and assesses how the observed values of the indicator

compare with another related measure. For example piloting the questionnaires by assessesing

35

the practicality and applicability of questions will ensure that they are clear, feasible and

unambiguous before using the final version for the main study participants

Construct Validity

Guyatt et al., (1993) describe this method as the most rigorous approach to establish validity.

Construct validity examines the logical relationship that exists between a measure and the

characteristics of the system being studied and also involves comparisons between the measures.

Sub-types of construct validity include convergent validity (positive correlation with a related

measure) and discriminate validity (low correlation coefficient) (Mallia-Milanes, 2010 ; Saw,

2001).

Reliability

The consistency and reproducibility of an instrument are the main parameters to be examined for

testing its reliability (Pinar, 2002, McLeod et al., 2008). This quality of the instrument is always

demonstrated by using internal consistency and test-retest reliability.

Sensitivity

The sensitivity of an instrument lies in its ability to detect small changes in parameters such as

approval times, milestones, quality measures and strategic goals (Mallia-Milanes, 2010;

Higginson and Carr, 2001 and McLeod et al, 2008).

DATA PROCESSING AND ANALYSIS

Data will be collected using electronic mail, postal mail, fax, interviewer delivered, computer

assisted telephone interviews and semi-structured interviews. Irrespective of the delivery

method, data will be entered into Microsoft Excel and developed specifically for each study.

Data processing and analysis will be carried out using Microsoft excel and the Statistical

Product and Service Solutions (SPSS). The sample mean will be used extensively for estimating

the population means (the 'middle' value), as was the median (the value halfway through the

ordered data set, below and above which there lies an equal number of data values).Where

applicable ranges around the median and average will be shown to indicate the spread of the

data. Scatter plot will be used to summarise data sets that are bivariate in order to give a good

visual picture of the relationship between the two variables. Box and Whisker plot will be used

on data sets measured on an interval scale to show the shape of the distribution, the central value

36

and variability. If the data is quantitative, descriptive statistics such as mean, median and range

will be used and if the data is qualitative, content analysis will be employed to generate themes

and sub-themes.

Quantitative Content

Hypothesis testing

Hypothesis testing refers to the process of choosing between competing hypotheses about a

probability distribution, based on observed data from the distribution. There are two types of

statistical hypotheses.

Null hypothesis: The null hypothesis, denoted by H0, is usually the hypothesis that sample

observations result purely from chance.

Alternative hypothesis: The alternative hypothesis, denoted by H1 or Ha, is the hypothesis that

sample observations are influenced by some non-random cause.

To perform hypothesis testing a theory needs to be presented that is believed to be true or is to be

used as a basis for an argument, but has not been proved. An example of a hypothesis could

be the claim that a new drug is better than the current drug for treatment of the same symptoms

(Easton and McColl. 2001). In each case two contrasting hypotheses are assessed: the null

hypothesis, denoted by H0 and alternative hypothesis denoted by H1. These two hypotheses are

not treated on an equal basis as special consideration is given to the null hypothesis. This is due

to the fact that the null hypothesis relates to the statement being tested, whereas alterative

hypothesis relates to the statement to be accepted if or when the null hypothesis is rejected

(Easton and McColl, 2001). Plausible arguments will be generated to test a series of hypotheses

arising from the aims and objectives of the study.

Hypothesis testing will be used to:

Evaluate the approval time in Oman

Evaluate the approval time in the GCC Centralised Procedure.

Evidence will be generated to test a series of hypotheses for each of these studies.

37

Choice of Statistical testing procedures

A statistical test provides a mechanism for making quantitative decisions about a process or

processes. The intent is to determine whether there is enough evidence to reject a conjecture or

hypothesis about the process. Therefore, statistical inferences make use of information from a

sample to draw conclusions (inferences) about the population from which the sample was taken

(Easton et al., 2001). The sample mean will be used extensively for estimating the population

means as will the median. Where applicable, ranges around the median and mean will be shown

to indicate the spread of the data. Scatter plots will be used to summarise data sets that are

bivariate (two variables) to give a good visual picture of the relationship between the two

variables. Box and whisker plots will be used on data sets measured on an interval scale to show

the shape of the distribution, the central value, and variability. The figure produced consists of

the most extreme values in the data set (5th

and 95th

percentile values), the lower and upper

quartiles (25th

and 75th

percentile values), and the median. Occasionally, pie charts will be used

for sets of categorical data, each segment representing a particular category and the area of each

segment being proportional to the number of cases in that category (Easton et al., 2001). Several

statistical tests will be used in the present study, depending on the research question asked, the

distribution of the data and the number and characteristics of the data set. For each analysis, the

test used will be specified.

Regression

In statistics, regression analysis is a statistical technique for estimating the relationships among

variables. It includes many techniques for modeling and analysing several variables, when the

focus is on the relationship between a dependent variable and one or more independent

variables. Regression analysis will be used to express the relationship between two (or more)

variables algebraically. The regression equation indicates the nature of the relationship between

two (or more) variables. In particular, it indicates the extent to which some variables can be

predicted by knowing others, or the extent to which some are associated with others. A linear

regression equation is usually written as Y = a + bX + e, where „Y‟ is the dependent variable, „a‟

is the intercept, „b‟ is the slope or regression coefficient, „X‟ is the independent variable (or

covariate) and „e‟ is the error term (Easton et al., 2001).

38

Correlation

Correlation analyses can be used to show the strength of a relationship between two variables. A

correlation coefficient, statistically referred to as r, is a number between -1 and 1 which measures

the degree to which two variables are linearly related. If there is a perfect linear relationship with

a positive slope between the two variables, the correlation coefficient equals +1. There is a

positive correlation whenever one variable has a high value and so does the other, or vice versa.

If there is a perfect linear relationship with a negative slope between the two variables, the

correlation coefficient equals -1. A correlation coefficient of 0 indicates that there is no linear

relationship between the variables (Easton et al., 2001).

Mann-Whitney U-test

The Mann-Whitney U-test is a non-parametric test used to test the difference between the

medians of two independent samples (Crichton, 2000a; Easton et al, 2001),for example males

and females.

Wilcoxon Signed Rank test

The Wilcoxon Signed Rank test is a non-parametric test used to test the median difference in

paired data (related samples). This test is the non-parametric equivalent of the paired t-test

(Crichton, 2000b; Easton et al., 2001).

Kruskal-Wallis test

The Kruskal-Wallis one-way analysis of variance (ANOVA) is a nonparametric test used to

compare three or more independent samples. It is used to test the null hypothesis that all

populations have identical distribution functions against the alternative hypothesis that at least

two of the samples differ only with respect to location. The outcome of this test is not conclusive

as to which of the samples differ. The Kruskal-Wallis test is a logical extension of the Mann-

Whitney U-Test (Easton et al, 2001).

Qualitative Content

The content analysis is a widely used qualitative research technique. Rather than being a single

method, current applications of content analysis show three distinct approaches: conventional,

directed, or summative. All three approaches are used to interpret meaning from the content of

39

text data and, hence, adhere to the naturalistic archetype. Content analysis does not proceed in a

linear fashion and is more complex and difficult than quantitative analysis because it is less

standardized and formulaic (Polit &Beck, 2004). Content analysis is a method of analysing

written, verbal or visual communication messages (Cole, 1988). It is also known as a method of

analysing documents allowing the researcher to test theoretical issues to enhance understanding

of the data.

This method also serves for making replicable and valid inferences from data to their context,

with the purpose of providing knowledge, new insights, a representation of facts and a practical

guide to action (Krippendorff 1980; Sandelowski, 1995). Miles & Huberman (1994) presents the

following three parallel flows of activity to explain the analysis.

Data Reduction: the process of selecting, focusing, simplifying, abstracting and

transforming the data. The purpose is to organize the data so that the final conclusion can

be drawn and verified.

Data display: taking the reduced data and displaying it in an organized compressed way

so that the conclusions can be more easily drawn.

Conclusion drawing/verification: deciding what things mean, noting regularities,

patterns, explanations, possible configurations, causl flows, and propositions.

Miles and Huberman (1994) further describe pattern coding as a way to present data for a

qualitative analysis, pattern coding is important since it reduces large amounts of data into a

smaller number of analytic units. Codes are tags or labels for assigning units of meaning to the

descriptive or inferential information compiled during a study. Codes are attached to “lumps” of

varying size – words, phrases, sentences, or whole paragraphs, connected or unconnected to a

specific setting‟ . This allows the researcher for a better focused analysis and helps to elaborate a

cognitive map in order to understand local incidents and interactions. Codes are used to retrieve

and organize the data which includes descriptive codes, interpretive codes, pattern code etc.

In this study, a set of steps is followed in order to analyze the generated data. The questionnaires

prepared are decided to be piloted with two GCC regulatory authorities before the

appropriateness of the final questionnaires is determined. Then they are e- mailed to the targeted

41

key regulators in the rest of the authorities for completion at pre-scheduled dates. The data

present in the completed questionnaires will then be analysed and reduced where the required

data is abstracted according to pre-set targeted information in individual GCC regulatory agency.

Furthermore, the data will be displayed in a report format where the respondent‟s answers will

be compared to one another in a clear organised manner. At the end the conclusions from the

analyses will be drawn based on patterns of similarities and dissimilarities which are revealed in

the data reduction and data display processes.

SUMMARY

The chapter describes the rationale for carrying out the study to evaluate the GCC

Centralised Procedure for the last ten years since its inception.

The various methodologies, techniques and instruments that will be used in analysing the

data obtained from the seven GCC regulatory authorities and the pharmaceutical

companies have been described.

A detailed description of the developmental technique of the two questionnaires was also

provided and how the information obtained from these questionnaires are reduced,

analysed and displayed in an organized manner.

Methodological choices related to database management, data processing and data

analyses were evaluated.

The data to be collected from the GCC States revolve around three major areas, namely,

the regulatory review processes and milestones, the registration timelines and the

stakeholders views‟ and experiences with GCC Centralised Procedur

41

CHAPTER 3

Evaluation of the Pharmaceutical Regulatory

Review Process in Oman

42

INTRODUCTION

The regulation of pharmaceuticals is mandated such that the government takes on responsibility

as the gatekeeper of the public‟s health and safety and it does this by regulating the behaviour of

the private sector for public purposes (Ratanawijitrasin 2002). Ensuring the safety, efficacy and

quality of medicines available to the public is the main aim of drug regulation. If regulatory

goals are to be achieved, appropriate structures must be established and the activities carried out

to achieve the desired goals.

Ideally, a government should endeavour to have a drug regulatory authority that is created by

comprehensive and up-to-date laws, is maintained as a unified but independent organisation,

contains competent human resources, is free from political and commercial influence, is

maintained by adequate and sustainable financial resources, is guided by transparent standards

and procedures, is driven by outcome-oriented implementation and is monitored and evaluated

systematically (Ratanawijitrasin 2002).

The time required by drug regulatory authorities to approve a new medicine may affect

healthcare professionals and patients and unnecessarily long approval times delay access to new

medicines that may improve the health status of patients (Rawson 2000). Oman had the

advantage of being the last country in the GCC to start adopting the registration system and as a

result the MOH review times decreased soon after the implementation of the new registration

guideline (Ministerial Decision (86/2000). Currently the registration decision must be within

four months from the date of first submission of the registration file. However, many factors still

affect the review process and delay product approvals e.g. lack of experts and resources.

This chapter evaluates the regulatory review process of new medicines in Oman and examines

the regulatory aspirations, barriers, problems and priorities, related to the review of new

medicines that could have an impact on their availability to patients. It assesses the current

regulatory situation in Oman in order to identify the key issues for improving review practices

and patients‟ access to new medicines.

43

OBJECTIVES

The objectives of this study were to:

1. Evaluate the regulatory review process in Oman and identify the milestones.

2. Review the regulatory timelines for pharmaceutical products in Oman between January

2006 and December 2010

3. Identify the strengths and weaknesses of the Oman regulatory review process.

4. Propose strategies that can improve the regulatory review process

METHODS

Data source

Information on the total application numbers and approval dates from January 2006 to December

2010 were obtained directly from the Oman Ministry of Health. This includes New Active

Substances (NASs), Existing Active Substances (EASs), biological products and vaccines. The

data also includes the application submission date, the registration date and the overall review

time. The products were classified into four groups (regions) according to the location of the

manufacturing companies (GCC, non-GCC Arab, international and Asian). A questionnaire for

studying the regulatory review process in the emerging markets was used in this research

(McAuslane et al. 2009). This questionnaire consisted of four parts namely, a review of the

regulatory review process, the requirements for submission of new drug applications, good

review practices, and the timeline for the review process.

Hypotheses

This study examined the following hypotheses:

1. There was an increase in the number of pharmaceutical products approved in Oman

between 2006 and 2010.

2. The largest number of products approved in Oman originated from international

companies.

3. There was a significant increase in the total approval time in Oman between 2006 and

2010.

4. The time of approval for products from the Gulf pharmaceutical companies was shorter

than for other companies.

44

5. There was a significant increase in New Active Substances (NASs) approval times in

Oman between 2006 and 2010.

6. There is no difference in approval times between major therapeutic groups for NASs.

DATA PROCESSING AND ANALYSIS

The data were processed using Excel and SPSS for windows. The statistical analysis for Existing

Active Substances (EASs) and New Active Substances (NASs) covered: the total number of

registered products between 2006 and 2010; and regulatory approval time in Oman between

2006 and 2010 for different cohorts of pharmaceutical products (GCC, non-GCC Arab,

international and Asian); different dosage forms (i.e. solids, semi-solids, liquids, injectables);

and different therapeutic indications (i.e. Cardiovascular system (CVS), Central nervous system

(CNS), Gastro-intestinal system, and Anti-Infectives). Non parametric tests were applied for the

analysis of the data presented in this chapter.

RESULTS

For the purpose of clarity the results will be presented in three parts:

Part I: Review process map and milestones.

Part II: Products reviewed and their characteristics.

Part III: Good review practices in the assessment and registration process.

Part I: Review process map and milestones

The review process map (figure 3.1) reflects the current situation of the Directorate General of

Pharmaceutical Affairs and Drug Control (DGPA&DC) and is a simplified representation of the

main steps being followed for the review of New Active Substances (NASs) and Existing Active

Substances (EASs). The map represents the review and authorisation of a product that is

approved on the first cycle and does not include a second cycle for products approved subject to

submission of additional data. The map also does not include the steps involved in the case of a

refusal of an application (such as hearing, appeal etc.)

The Drug Control and Quality Control Laboratory Departments in DGPA&DC are responsible

for reviewing the marketing authorisation applications. The two departments currently have a

staff of 43 people, 22 of whom are involved in the process of review. There is no formal „fast

45

track‟ procedure, however, life saving medicines are not queued but are selected for review as a

priority, although, the data requirements and review process are the same. The process map and

milestones for Oman is shown in figure 3.1. The review process milestones in the review and

approval are as follows;

a) The receipt and validation stage: This includes administrative registration (reference

number) and validation of legal requirements, the status of the company, details of the

local agent and manufacturer as well as a „checklist‟ validation of the application content

(e.g. technical sections, CPP status). The product applications received are duly recorded

electronically which then generate a unique tracking number. After receiving the product

file, the company must pay the registration fee within one week. The file is rejected if the

information is not complete and a new application must be made after completing the

missing data. The time required for the receipt and validation procedures is only one day.

b) Queuing for review: Once the file is accepted, it will be entered into a queue for review

which takes around one week. The product dossier is divided into two parts; the safety

and efficacy part which are reviewed by the Drug Control Department and quality by the

Quality Control Laboratory. Administrative time is a measure of the „backlog‟ time while

valid applications queue for commencement of their review.

c) Scientific review: Scientific review and analysis takes three months to complete for the

Drug Control Department and Quality Control Laboratory, although both proceed in

parallel. The start and finish of the scientific assessment is formally recorded. The QC

laboratory sends the quality assessment report to the Drug Control Department where the

reviewer, after completing a scientific product report form, submits the file to the

Technical Committee for Registration of Pharmaceutical Manufacturers & Their Products

& Pricing (TCR&P) for a decision.

46

Figure 3.1 PROCESS MAP FOR SULTANATE OF OMAN

(A) RECEIVING OF APPLICATION (B) ACCEPTED FOR REVIEW

(C) SCIENTIFIC REVIEW STARTS (D) Start of Registration Committee Procedure (E) QUESTIONS TO COMPANY REGISTRATION REJECTION

Receipt & Validation Procedures Validation Time: 1 day

Queuing for review Administration Time: 2 weeks

Safety Efficacy Sample

analysis

Quality

Assessment Time: 3 months

Drug Control Department Quality Control Department

<<< Parallel review >>>

Discussion in Technical Committee for Registration of Pharmaceutical

Manufacturers & their Products and Pricing of those products Meets

every

2

weeks

Assessment Time: 1 month

Questions Processed by Company

Reply from Company

TCR&P

REGISTRATION

Company Time: 1 -6 months (Clock stop)

Assessment time: 1 month

Overall registratio

n tim

e 4

mo

nth

s

47

d) Registration committee procedure: The registration committee meets routinely every

two weeks. The TCR&P, established by the Minister of Health, consists of members

from two different directorates of the Ministry of Health, six members from DGPA&DC

and two members from the Directorate General Medical Supplies. All of the members

are Pharmacists and there are no external members. The company can meet with the

internal directorate staff to discuss questions and queries that arise during the assessment,

but they are only permitted to meet the Director and/or Section Heads. If the committee is

satisfied with the safety profile of the product, it will be registered, otherwise rejected. If

registered, a Product Registration Certificate signed by the Chairperson of TCR&P is

issued within two weeks from the date of registration. In the case of a rejection, the

company can appeal within two months from the date of receiving the Committee's

rejection decision.

e) Questions to the companies: In the case of any queries raised by the Committee, they

will be conveyed by the Committee Secretary to the company to respond within a

stipulated deadline which is normally given from 1 to 6 months. Once the response from

the company is received within this stipulated deadline, it is discussed in TCR&P within

one month from the date of its receipt and accordingly a final decision is taken. The issue

of product authorisation also depends on the pricing agreement and discussion of pricing

is separate from the technical review but does not delay the approval of products. The

pricing negotiation starts after the end of the scientific review.

Models of regulatory review:

Many authorities apply different levels of data assessment to different applications, according to

the type of product and/or its regulatory status with other authorities. Three basic types of

review models for the scientific assessment have been identified as a result of discussions with

regulatory authorities and workshop reports from CMR International Institute for Regulatory

Science (McAuslane, 2006), namely,

1. Verification model (type I assessment)

2. Abridged model (type II assessment)

3. Full review model (type III assessment)

48

Verification model (type I assessment)

This model is used to reduce duplication of effort by agreeing that the importing country will

allow certain products to be marketed locally once they have been authorized by two or more

recognized reference agencies, elsewhere. The main responsibility of the authority in the

importing country is to „verify‟ that the product intended for local sale has been duly registered

as declared in the application and that the product characteristics (formulation, composition) and

the prescribing information (use, dosage, precautions) for local marketing conforms to that

agreed in the reference authorization(s).

Abridged model (type II assessment)

This model conserves resources, by not re-assessing scientific supporting data that has been

reviewed and accepted elsewhere but includes an „abridged‟ independent review of the product

in terms of its use under local conditions. This might include a review of the Chemical and

Manufacturing Control (CMC) data in relation to climatic conditions and distribution

infrastructure and a benefit-risk assessment in relation to use in the local ethnic population,

medical practice/culture and patterns of disease and nutrition. Approval by a recognized agency

elsewhere is a pre-requisite before the local authorization can be granted but the initial

application need not necessarily be delayed until formal documentation such as a Certificate of a

Pharmaceutical Product (CPP) is available.

Full review model (type III assessment)

In this model the authority has suitable resources, including access to appropriate internal and

external experts, to carry out a „full‟ review and evaluation of the supporting scientific data

(quality, pre-clinical, clinical) for a major application. A Type III assessment could be carried

out on a new application that has not been approved elsewhere but in practice legal requirements

may dictate that the product must be authorized by a reference authority before the local

authorization can be finalized. The module used by Oman in the assessment of all major

application is an Abridged Assessment. Oman MOH is capable to conduct an independent

review of product applications. However, Oman carries out a unique practice whereby the New

Active Substances (NASs), being considered for approval, must be marketed in the product

country of origin for at least 24 months before it can be registered in Oman. This requirement

may be waived, depending on the product type, if evidence of registration in recognized

49

international reference agencies such United States Food and Drug Administration (US FDA),

European Medicines Agency (EMA) and/or GCC Centralised Drug Registration (GCC-DR)

System.

Part II: Products considered and their characteristics

Approval of all products in Oman (2006 - 2010)

A total of 807 pharmaceutical products for human use were successfully registered in Oman

between 2006 and 2010 (Figure 3.2). This number included EASs and NASs with a similar

portion for the years 2006, 2008, 2009 and 2010 (176; 22%; 171; 21%; 172; 21%; and 178; 22%,

respectively), but there was dip in 2007 (110; 15%).

Figure 3.2: Total number of pharmaceutical products approved in Oman (2006-2010)

Statistical analysis of these data using a simple linear regression showed no significant increase in the total number

of registered pharmaceutical products over the five year period (p>0.05).

This was possibly due to the development of new regulations for the approval of health products

and alternative medicines. These new regulations resulted in an overload for the Quality Control

Laboratory, increasing the analysis time required for pharmaceutical products. The results

showed no significant increase (p>0.05) in the total number of registered pharmaceutical

products from 2006 to 2010 (Figure 3.2).

0

20

40

60

80

100

120

140

160

180

200

2006 2007 2008 2009 2010

Nu

mb

er

of

pro

du

cts

Registration Year

Number of product Line of best fit

51

Approval of Existing Active Substances (EASs) and New Active Substances

(NASs) in Oman (2006 – 2010)

The total number of products registered in Oman between 2006 and 2010 was 807 and this

included 573 EASs and 234 NASs. The highest number of EASs registered in Oman was seen in

year 2010 (137) followed by year 2008 (123), year 2009 (116) year 2006 (112) and year 2007

(87) (Figure 3.3). Statistical analysis using a simple linear regression showed a significant

increase in EASs registered over the five year period (p<0.001).

Figure 3.3: Number of EASs approved in Oman for the period (2006-2010)

Statistical analysis using a simple linear regression showed a significant increase in EASs registered over the five

year period, (p<0.001).

The highest number of NASs was registred in 2006 (64; 36%), while the lowest number was in

year 2007 (25; 23%) (Figure 3.4). From these 234 NASs, 226 (97%) were found to be from

international companies. Statistical analysis using a simple linear regression showed a significant

increase in the number of registered EASs with a significant decrease in the number of registered

NASs (p<0.001).

0

20

40

60

80

100

120

140

160

Num

ber o

f Pro

duct

s

Registration Year

EASs Line of best fit

51

Figure 3.4: Number of NASs approved in Oman for the period (2006-2010)

Statistical analysis using a simple linear regression showed a significant decrease in the number of registered

NASs over the five year period (p<0.001).

The number of pharmaceutical products registered for international, GCC,

non-GCC Arab and Asian companies (2006-2010)

The number of products registered during the five years period varied for different cohorts of

companies based on their geographical location, for example the highest number was for the

international companies products (393; 49%), followed by the GCC Companies products (962;

33%), non-GCC Arab Companies products (95; 12%) and Asian Companies products (50; 6%)

(Figure 3.5).

The Existing Active Substances (EASs) approved for GCC, international non-

GCC Arab and Asian companies in Oman (2006-2010)

A total of 573 Existing Active Substances (EASs) were registered in Oman between 2006 and

2010. When examined by individual regions 267(47%) medicines were identified as being

approved from GCC, 167(29%) from international companies, 94 (16%) from non-GCC Arab,

and 45 (8%) from Asian companies. Statistical analysis of the data using Kruskal-Wallis Test

(K-Test) over the five-year period showed that there was a significant increase in the number of

registered Existing Active Substances (EASs) between 2006 and 2010 (p<0.001).

0

10

20

30

40

50

60

70

Num

ber o

f Pro

duct

s

Registration Year

NASs Line of best fit

52

Figure 3.5: Approved pharmaceutical products (EASs & NASs) for GCC, international, non-GCC

Arab and Asian companies (2006-2010)

Approval times of all pharmaceutical products in Oman (2006 – 2010)

The total approval times for pharmaceutical products in Oman for the period of the study (2006 -

2010) was calculated for all of the 807 Existing Active Substances (EASs) and New Active

Substances (NASs) from different pharmaceutical companies. The median approval time varied

from 55 days in 2006 to 207 in 2008 while in 2010 it was 138 days showing a 33% decrease in

the approval time(Figure 3.6). Statistical analysis using Kruskal-Wallis Test (K-Test) over the

five-year period showed that there was a significant increase in approval times for

pharmaceutical products from 2006 to 2010 (p<0.001).

Approval time for Existing Active Substances (EASs) in Oman (2006 - 2010)

Approval time for 573 Existing Active Substances (EASs) registered in Oman varied over the

period (2006-2010) (Figure 3.7). The lowest median in this period was seen for 2006 (39 days)

and the highest median for 2009 (176 days). Statistical analysis using Kruskal-Wallis Test (K-

Test) over the five-year period showed that there was a significant upward trend in the median

approval time (39, 93, 149, 176 and 138 days respectively) for EASs between 2006 to 2010

(p<0.001).

53

Figure 3.6: Median approval time for all pharmaceutical products in Oman (2006-2010)

Statistical analysis using Kruskal-Wallis Test (K-Test) showed that there was a significant increase in approval

times for pharmaceutical products from 2006 to 2010 (p<0.001).

Figure 3.7: Median approval time for Existing Active Substance (EASs) in Oman (2006-2010)

Statistical analysis of the data using non-parametric K- test shows a significant upward trend in the median

approval time over the five year period (P<0.001).

54

Approval time for New Active Substances (NASs) in Oman (2006 - 2010)

The highest number of products (64) was registered in the year 2006 with the median approval

time of 72 days followed by 133 days for 25 products in 2007 and 292 days for 48 products in

2008. In year 2009, 56 products were registered with a median approval time of 147 days and

159 days for 41products in 2010. The drop in the number of registered products in year 2007

was due to the development of the new regulations for approval of health and alternative

products. These new regulations created an overload for the Quality Control Laboratory,

increasing the time of analysis of pharmaceutical products. The results obtained from performing

analysis of variance test showed that there was a significant upward trend in the median approval

time for NASs products between 2006 and 2010 (p<0.05). (Figure 3.8)

Figure 3.8: Median approval time for NASs in Oman (2006-2010)

The results of variance test analysis showed that there was a significant upward trend in the median approval time

between 2006 and 2010 (p<0.05).

Approval time for Existing Active Substances (EASs) submitted by GCC,

international, non-GCC Arab and Asian companies (2006-2010)

The median approval time for different cohorts of companies varied from 80 for the GCC

companies to 254 for the Asian companies (Figures 3.9). The rapid approval time for the GCC

States is due to their efforts; particularly Oman, Saudi Arabia, UAE, and Kuwait, to improve

55

their local manufacturing capabilities and the production capacity for the local population. EASs

from Asian companies had the longest median approval time of 254 days. Statistical analysis of

the data using non-parametric K- test showed that there was a significant difference in approval

times between different cohorts of companies (P<0.001).

Figure 3.9: Median approval time for GCC, international, non-GCC Arab, and Asian companies

Existing Active Substances (EASs) in Oman (2006-2010).

Statistical analysis of the data using non-parametric K- test showed a significant difference in approval time

between different cohorts of companies (P<0.001).

Approval time for different dosage forms for all Existing Active Substances

(EASs) and New Active Substances (NASs) in Oman, (2006-2010)

During the five years, 573 EASs were registered in Oman with the lowest number represented by

the semi-solid dosage forms (48) followed by injectables, liquid dosage forms and the highest

number was represented by solid dosage forms (364). Out of 234 NASs registered, the lowest

number is represented by the semi-solid dosage forms (3) with a median approval times of 73

days and the highest by the solid dosage forms both in term of numbers (121) and median

approval time (145 days) (Figure 3.10).

0

50

100

150

200

250

300

Gulf International Arab Asian

Tota

l Med

ian

App

rova

l Tim

e (D

ays)

Company Type

Median Time

56

Figure 3.10 Median approval time for different dosage forms for EASs and NASs in Oman,

(2006-2010)

Approval times for Existing Active Substances (EASs) and New Active

Substances (NASs) by therapeutic class, (2006-2010)

An examination of EASs by therapeutic class showed that the lowest number was represented by

the immunological preparations (1 preparation) and the highest number by the injectables (117

preparations). The analysis of the approval time of EASs registered between 2006 and 2010

involved the four major therapeutic groups which dominate the pharmaceutical market in Oman,

namely,

The cardiovascular system (CVS)

The central nervous system (CNS)

The gastro-intestinal system

Anti-Infectives

The range of median approval times for EASs analysed by therapeutic class varied from 141

calendar days for CNS products to 57 for gastro-intestinal products. The differing patterns of

approval times for EASs from different therapeutic groups were attributed to the authority‟s

assessment requirements which may or may not include the need for clinical and bioequivalent

studies. This can be a lengthy process and has an impact on the overall approval timeline.

57

Another reason for such differences is the sponsor‟s response time to the authority‟s request and

the level of communication between the two parties. During the period of study, 234 NASs were

approved in Oman, with the lowest number represented by the ear, nose and oro-larynx

preparations (1) and the highest number by cardiovascular preparations (40). Figure 3.11 shows

the range of approval times for NASs analysed by therapeutic class and these varied from 216

days for anti-infectives to 49 for gastro-intestinal products.

Figure 3.11: Median approval times for different therapeutic classes for EASs and NASs in Oman

(2006-2010)

There were several factors leading to the variation in approval times for different therapeutic

groups. In some cases, consultations with different therapeutic committees within the Ministry of

Health, for example Central Drug Committee (CDC) and National Antibiotic committee, which

do not have regular meetings, may have caused delays in the approval time. Some medicines

have longer pricing times due to a protracted period of negotiation with the companies.

Part III: Good review practice in the assessment and registration process

The ultimate measure of success in regulatory performance is the quality reviews and decisions,

as well as the quality of the dossiers (Kendle, 2009; Karlton and Johnson, 1997 and McAuslane

and Cone, 2006). The regulatory authority, industry and patients benefit from having a high

quality review process that is well managed (Hynes et al., 2001 and Booz Allen Hamilton, 2008).

58

An efficient review allows the regulatory authorities to fulfill their public health mission to

ensure that safe and effective medicines are made available to patients in a timely manner and

allows for efficient use of resources. Patients benefit from the timely access to safe and effective

therapies while pharmaceutical companies are able to market the product sooner and generate

revenues (Booz Allen Hamilton, 2008). The regulatory challenge is to allow access to the safest

and most effective pharmaceutical products in the shortest possible time with a highest degree of

certainty (Alder, 2001).The results showed that the Oman regulatory authority, the Directorate

General of Pharmaceutical Affairs & Drug Control (DGPA&DC), intends to implement a

number of quality measures in the review and authorisation of medicinal products. It includes a

well defined internal quality policy, good review practices, standard operating procedures,

assessment templates and a peer review process.

General measures used to achieve quality

The DGPA&DC currently does not have an internal quality policy which defines the intentions

and directions of the organisation related to quality as formally expressed by top management.

But it is likely to be established in the near future. Similarly, good review practices are not

formally documented at present but will be established soon. A well defined code about the

process and documentation of review procedures would standardize and improve the overall

documentation and ensure timeliness, predictability, consistency and high quality reviews.

Standard operating procedures were implemented in the DGPA&DC for certain procedures

while for the remaining processes, SOPs will soon be established. Assessment templates would

set out the content and format of written reports on scientific reviews however they are not in use

currently but are likely to be established within the next few years. A peer review procedure is

currently used for vaccines as there are two committees reviewing the vaccines marketing

authorisation applications. Peer review, defined as an additional evaluation of the original

assessment that is carried out by an independent person or committee, is unlikely to be

established in the next few years.

Quality management

The three most important measures which the DGPA&DC identified for establishing quality

measures were (1) to be most efficient, (2) to minimise errors and (3) to increase transparency.

59

To improve quality, the following activities were undertaken to bring about continuous

improvement in the assessment and authorisation process:

Reviewing stakeholders‟ feedback (e.g. through complaints, meetings or workshops) and

taking necessary action.

Carrying out internal quality audits (e.g. self assessments) and using the findings to

improve the system.

Having external quality audits by an accredited certification body to improve the system

(e.g. WHO)

The DGPA&DC does not have a dedicated department for assessing and/or ensuring quality in

the assessment and registration process for new medicines, however, there are plans to set up

such a department in the future.

Quality in the review and assessment process

The guidelines issued under the Ministerial Decision No. 86/2000 serve as an official document

to assist the industry in the registration of medicinal products in Oman. This Ministerial Decision

is also available on the Ministry of Health website. Pre-application scientific advice is not

available to applicants, but can be obtained during the file submission day. The applicants are

allowed to make formal contacts with DGPA&DC staff to discuss an application during its

review process.

There is a registration committee called “The Technical Committee for Registration of

Pharmaceutical Companies and their Products and Pricing”. The committee consists of eight

members and meets once every two weeks. New Active Substances (NASs) applications are

reviewed by this committee while Major Line Extensions (MLE) are reviewed by the Drug

Control Department in the DGPA&DC and not forwarded to the registration committee. The

committee receives assessment reports from the Drug Control and Quality Control Laboratory

staff that review the applications. Shared/Joint reviews are undertaken when products are

submitted through the GCC Central Registration Procedure.

61

Training and continuing education

To maintain or improve the quality of the work, it is essential that reviewers follow training or

refresher courses from time to time. These may concern general training about new

developments in the regulatory science field or specialized training in carrying out a quality

review process. The DGPA&DC does not currently have any formal training programmes for

assessors. Training is mainly carried out through external courses, post-graduate degrees,

participation in international workshops/conferences, placements and secondments in other

regulatory agencies and inviting speakers to the authority. After training or attending a course,

the reviewer should report and convey his/her experience or knowledge to colleagues and top

managers and make proposals for any change of existing procedures or adoption of new

practices to improve the overall performance of the reviewing staff.

Transparency of the review procedure

The DGPA&DC assigns a high priority to transparency of the review procedure. It has identified

the following three top incentives for assigning resources to activities that enhance the openness

of the regulatory system namely: political will, the need to increase confidence in the system and

to provide assurances to the pharmaceutical industry. Information such as product approval and

the price of medicines is routinely provided to the general public. The information can be

accessed from the ministry‟s official website or provided on submission of a formal request. As

far as transparency is concerned, the companies can follow up the progress of their application

either through phone contact, email or meetings with the officials with prior appointment. There

is an electronic system for registration and tracking of applications, which also can be used to:

Track applications that are under review and identify the stage of the process

Signal that target review dates have been exceeded

Record the terms of the authorisation once granted

Archive information on applications in a way that can be retrieved.

Drivers and barriers facing the review process in Oman

Understanding the drivers and barriers to achieving a quality regulatory review process can

promote innovative and creative ideas and practices to help reviewers assess new products and

underline the importance of monitoring the quality of the review process.

61

There are several motivating factors identified by DGPA&DC that contribute to accomplishing

the desired effectiveness and efficiency of the authority‟s review procedures and decision-

making for new applications, namely:

Good tracking system

Utilization of an assessment template.

Good Management Plan

Well qualified, trained and experienced reviewers

However, the DGPA&DC is facing several obstacles that are hindering its ability to ensure that

new medicines are available in a timely manner, i.e:

Shortage of experience personnel

Lack of an independent budget

Lack of an internal quality policy

DISCUSSION

This study has evaluated the pattern of total regulatory approval time in Oman between 2006 and

2010. It has also addressed the various factors which may have a positive or negative effect on

the total approval time. It has been shown that the total number of registered Pharmaceutical

Products in Oman (2006 - 2010) is 807 and this number includes Existing Active Substances

(EASs) and New Active Substances (NASs).

Six hypotheses were generated for this study, as outlined previously and the findings are

discussed below.

1) There was an increase in the number of pharmaceutical products

approved in Oman between 2006 and 2010.

The largest number of registered medicines was found in 2006. In this year, there was no

overload on the quality control laboratory since the actual approval of health products, using the

recent guidelines and regulations (Circular 64/2005) did not start until 2005. However, the

number of the registered medicines was similar in the years 2006, 2008 & 2009 with the

exception of 2007 when there was a fall. This was largely due to the development of new

regulations for approval of health products. These new regulations resulted in an overload on the

62

Quality Control Laboratory, increasing the time of analysis of pharmaceutical products. This

hypothesis has therefore rejected.

2) The largest number of the products approved in Oman originated from

international companies.

The number of products registered during the five year period (2006-2010) varied for different

companies based on their geographical location. The largest number was for the international

companies products, followed by the GCC companies, non-GCC Arab, and finally the Asian

companies. International companies were the largest group registering products every year in

Oman. This was due to the fact that the pharmaceutical companies must submit a full registration

application when the manufacturing site has been changed for the same registered company.

Thus, there was an increase in the number of changes in product manufacturing sources

applications from the international companies during this five year period. Furthermore,

international companies increased the number of their submissions to the Omani authority to

obtain registration approval as evidence that would support their GCC-DR approval. The pricing

process in Oman is the final step and price negotiations occur at the end of the scientific

assessment. The Registration Committee makes the decision on the product registration and

pricing. Oman has a robust pricing control system and this is one of the main reasons that

pharmaceutical companies register their products in Oman prior to other GCC states. Using a

price reference system, the pricing committee considers the manufacturer's wholesale and retail

prices in the country of origin, export Cost-Insurance-Freight (CIF) prices to Oman as well as

CIF prices in other GCC states. This hypothesis was accepted.

3) There was a significant increase in the total approval time for medicines in

Oman between 2006 and 2010.

During the five years, the median approval time varied from 55 days in 2006 to 119 days in

2010. There was a significant increase in the median approval time between 2006 and 2008

which was due to the new regulations that were implemented by Oman MOH in 2006 for the

registration of human health products. This was due to the increase in the number of local

registration applications and the applications received from GCC-DR for Oman MOH

evaluations. Registration for the pharmaceutical companies and their products must be renewed

every five years as required by the Oman registration system. In 2006 Oman MOH requested

63

pharmaceutical companies to re-register their products. This re-registration was for the first time

and led to an increase in the number of applications and an overload for the Drug Control

Department and Quality Control Laboratory.

The WHO has clearly stated that the shortage of qualified personnel is the greatest problem

faced by drug regulatory authorities (WHO, 2003a), and is one of the factors affecting patients‟

access to new medicines in Oman. All staff are paid according to established salary bands for the

entire public service. Consequently, Oman MOH is unable to use salaries to attract and retain

some of the skills that would strengthen the regulatory role. This hypothesis was therefore

accepted.

4) The time of approval for products from Gulf pharmaceutical companies

was shorter than other companies.

Median approval time varied for different companies from 80 to 254 days for GCC and Asian

companies respectively. The rapid approval time is mainly due to the GCC States making efforts,

particularly Oman, Saudi Arabia, UAE, and Kuwait, to improve their local manufacturing

capabilities and the production capacity for the local population (Al-Essa, 2011). This led to a

positive outcome in approval times, giving a median time of 80 days. There are other factors

which have a positive effect on the approval time for local and Gulf companies but have a

negative effect on the international, non-GCC Arab and Asian companies. For example, in

decision-making, the geographical proximity of the company to the authority leads to an

effective interaction and thus a faster response to any questions from the authority. Additionally,

most locally manufactured products are EASs and do not need very much consultation during the

scientific review compared to NASs. Furthermore, an understanding of the culture of the

regulatory authority where there is no language barrier has a positive effect on the review

process. However, a priority procedure is a common practice in many authorities, but often in

relation to the importance of the medicine rather than geographic location. In Canada and

Australia, pharmaceutical companies can apply to receive a priority review for their medicines

and the regulatory authority then decides which medicines will be reviewed in this way. The

FDA classifies all new medicine applications to receive either a priority or a standard review

(Rawson et al., 2000a). In this study, it was found that the 31% of the products, which received

priority approval, were manufactured by local companies or were for serious life-threatening

64

medical groups, e.g. cancer medicines. For the 5-year study period, products from Asian

companies had the longest median approval time of 254 days. Oman requests limited clinical

data in the form of bioequivalence studies to demonstrate that the EAS is bioequivalent to the

original product. Bioequivalence presents the first challenge for the EAS registration because

many manufacturers find it difficult and costly to perform high standard controlled trials that

compare the proposed EAS with the original product. Meanwhile, for EAS‟s the laboratory

sample analysis is carried out in parallel with the scientific review but the analytical step can be

waived if the product is registered in Saudi Arabia, UAE, and/or Kuwait, which have recognized

laboratories in the region. From these results this hypothesis has confirmed.

5) There was a significant increase in New Active Substances (NASs)

approval time in Oman between 2006 and 2010.

The pricing process can markedly affect the registration time in Oman. The pricing time for

NASs is longer than for EASs due to the period of negotiation. The registration committee sets

the lowest possible price for the original brand product, which is usually the export price to the

Saudi market. Saudi Arabia has much better negotiating power and hence the Omani agency

wants to use this power to reduce the medicine prices. Pricing is the final step and no product

will be issued a registration certificate before it is priced, but that proposed by the company is

not necessarily agreed, although the company is given an opportunity to appeal before the final

price is decided. Pricing negotiations start after the granting of registration approval of the

medicine. This approach prevents the pricing step from being integrated into the review process

and this delays the final approval time. Therefore, it would be preferable for the pricing process

to be carried out in parallel with the review process rather than after granting registration

approval. The analytical step is one of the approval requirements and takes up to almost 50% of

the total approval time for all companies. Unlike Oman, none of the international authorities

analyse the products pre-registration. Therefore, it is recommended that this step be carried out

post-approval with product samples being selected from the market for analysis. This would

reduce the registration time. Another inappropriate milestone is the submission of a Certificate of

pharmaceutical Product and the price certificate which has to be legalized by the relevant

authority and Oman embassy in the country of origin. Such regulations lead to registration delays

and increase the burden for the companies and it is not a WHO requirement.

65

The findings from this study indicate that the company time for answering questions from the

authority when companies submit analytical data are longer than the authority time for all

cohorts of companies. No doubt this issue also causes a further delay in the registration of

products, which affects patients‟ access to medicines submitted by international companies.

Furthermore, the delay caused by companies leads to a waste of authority time and resources. In

order to reduce the company time, it is recommended to implement an official clock-stop system

by the Omani health authority while the company respondes. This hypothesis was accepted.

6) There is no difference in approval time between major therapeutic groups

for the NASs.

The results of this study shows that there are significant differences in the approval time between

therapeutic groups, for example the approval time for the anti-infectives is three times longer

than those for gastrointestinal products. There are several factors leading to these differences in

approval times. In some cases, consultations with different therapeutic committees within the

Ministry of Health for example the Central Drug Committee (CDC) and the National Antibiotic

committee may cause delays in the approval time. In addition, the nature of the products

evaluated, e.g. biological products may require a more detailed review than others. Some

medicines have longer pricing time due to periods of protracted negotiations. Using a price

reference system, the pricing committee considers the manufacturers wholesale and retail prices

in the country of origin, export CIF (Cost, Insurance, and Freight) prices to Oman and CIF prices

in other GCC states. These results do not support this hypothesis.

CONCLUSIONS

This study has assessed the trend in the regulatory approval times in Oman for the period 2006 to

2010. The findings show that although there is an increase in the approval time for all

pharmaceutical company products, the median approval time for the five year period was 117

calendar days. This is within the time limit (4 months) which is fixed by the health authority for

the overall registration time. It was found that products in the different cohorts of companies,

which include local, GCC, non-GCC Arab and international companies have varying approval

times which may be due to an internal unpublished policy of prioritization within the authority.

However, there are many factors affecting the approval time, which include the quality of the

66

dossier, the geographical location of the company, communication within companies and various

cultural factors. This study enabled the regulatory authority in Oman to be made aware of its

own review time and the timing of each step within the process. Furthermore, since this study

was based on regulatory authority data, a reliable and accurate source, it may enable

pharmaceutical companies to better understand the factors that influence the review process and

the overall review time. This, in turn, may help to accelerate the registration procedure and save

time and resources by allowing a more rapid access to innovative medicines. The companies

have the responsibility for most of the delay of their own product registration in Oman because

they take a long time to respond to questions asked by the authority or to submit the analytical

data.

SUMMARY

The review time for the registration process during the period 2006 to 2010 is within the

time limit fixed by the Oman health authority, but there has been an upward trend in

regulatory approval times since 9206.

The total approval time varies according to the geographical location of the company,

and it was found that the shortest approval time was for products from local and Gulf

companies.

In addition to the factors already mentioned, the absence of separate sections for health

products and herbal preparations in the Drug Control and Quality Control Laboratory

Departments and the large number of samples to be analysed by the QCL from

Directorate of medical supplies has a significant impact on total approval time.

The pricing process for the NASs, the pre-registration analysis, lack of official clock-

stop system and the delay in replying to regulatory queries, all have a delaying impact on

approval time.

The fees for the registration of the companies and their products are very low in Oman.

This has led to a high number of applications and an increase in the median time of

registration.

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CHAPTER 4

Evaluation of Regulatory Review Times

in the Gulf States

68

INTRODUCTION

Long regulatory approval timelines for new medicines delay their access to the market that may

have the potential to improve patients' health status and of alleviating suffering. Variation in the

availability of medicines in different countries has been studied since the early 1970s (Rawson,

2000), and some marked differences have been identified. Regulatory approval time is a key

metric that is used to evaluate the performance of regulatory agencies (Hirako et al., 2007). A

study was previously made to evaluate the milestones and timelines involved in the regulatory

review processes for different authorities (Hirako et al., 2007). A specific study of the Gulf

regulatory authorities (Hashan, 2005) highlighted important aspects of the drug approval

procedures in each of the seven member states. However, the study provided limited information

about the approval timelines and the duration of the milestones and stages involved in the review

process because the authorities did not have electronic tracking systems to monitor such

activities. This made it difficult, if not impossible, to allow cohorts of pharmaceutical products to

be monitored retrospectively (Al-Essa, 2011).

Currently, within the GCC States, there are two registration systems, the national and the

centralised procedure. In order to benchmark and make true comparisons between the different

authorities, it is essential to identify first the common processes that occur during registration.

However, there are no major differences in the legislation, regulations or requirements for

marketing pharmaceutical products in the GCC States (Bahrain, Kuwait Oman, Qatar, Saudi

Arabia, UAE and Yemen). All the national regulatory departments in the GCC States have

regulations that govern and regulate most aspects of the pharmaceutical services by effective

laws (Hashan, 1998). Apart from the registration process of medicinal products, some countries

have price control also, in their remit.

It is recognized that individual authorities have different experiences and knowledge that could

be of value to other member states through comparison of various systems and sharing of best

practices to the benefit of all. To this effect, this study was conducted to explore the timelines of

the approval processes in the GCC States. However, it is important to have a basic understanding

of the regulatory review process in these countries in order to place the approval time in an

appropriate context.

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OBJECTIVES

The major objectives of this study are to:

1. Compare the number of registration applications submitted for pharmaceutical products over

the three-year period from January 2008 to December 2010 in the GCC States.

2. Compare the regulatory approval times for registered products for Gulf, Arab non-Gulf,

Asian and International pharmaceutical companies in the GCC States.

3. Assess the trends in approval times over the period 2008-2010.

4. Identify areas of the approval process in each of the seven Gulf States which might lead to

delays in the registration of new medicines.

5. Provide possible solutions for addressing the delays in the registration timelines in the Gulf

States.

METHODS

Participants

The participants were the authorities responsible for the regulation of pharmaceutical products in

the GCC States (i.e. (Bahrain, Kuwait Oman, Qatar and Saudi Arabia) Yemen was excluded

from this study because they could not provide data due to the unstable political situation in the

country during the period of this study. The United Arab Emirates was also excluded from this

study, as they are unable to furnish the full data due to changes in the drug regulatory

organization that took place during the time this study was conducted. Additionally, they were

also unable to extract some of the data as it was manually stored making retrieval of the required

information very difficult.

Data collection

A face-to-face meeting with all the Directors and General Directors of Regulatory Affairs in the

Ministry of Health in the GCC States took place during the GCC-DR meetings in 2011and 2012.

They provided the data on approval timelines as an Excel spreadsheet including the registration

data for products approved in 2008, 2009 and 2010, based on the milestones in each authority.

Clarification regarding the data set was obtained from the five authorities during 2012 through

telephonic conferences and electronic mails.

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The data consisting of all products from Gulf, Arab non-Gulf, Asian and International

manufacturers, approved for human use in 2008, 2009 and 2010 in the GCC States, were

included in this study. Products reviewed included both New Active Substances (NASs) and

Existing Active Substances (EASs) and only those with a complete data set e.g. submission date

and approval date were included in the analyses. In addition, relevant information regarding the

regulatory review process of the five Gulf countries was collected by literature search. The

overall data includes milestone and tables reflecting the specific characteristic of each system

(Al-Essa et al, 2012).

Models of regulatory review:

Three GCC authorities utilize an abridged assessment (Bahrain, Oman and Qatar) as describe in

chapter three. This is a critical practice to ensure the appropriateness of the product under local

conditions. Bahrain uses a verification review for biological and biotech products because they

have to be registered in other reference authorities to be accepted for review in Bahrain, and an

abridged review for other major applications. Saudi Arabia is the only country that performs a

full review on all types of applications, while Kuwait carry out a simple verification review on

the registration dossiers.

DATA PROCESSING AND ANALYSIS

The Regulatory approval times were calculated as the time from submission of the product

dossier to the regulatory authority until the final approval. The data sets processed include: the

total number of registered products between 2008 and 2010 and regulatory approval time in

GCC States between 2008 and 2010 for different groups of pharmaceutical products (GCC, non-

GCC Arabs, International and Asian). Descriptive statistics including frequencies was used to

present the results.

RESULTS

The results of this study are presented in two parts,

Part 1: Includes the process maps for the regulatory reviews in each of the five states together

with characteristics of the review process.

Part 2: The results are presented under three headings:

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I: Total number of product approved in each Gulf states.

II: Median approval times for the Gulf States by year 2008-2010

III: Median approval times for the different pharmaceutical companies.

Part 1: The regulatory process maps for the Gulf States:

All the GCC authorities share similar goals and obligations to safeguard public health when

assessing the safety, quality and efficacy of medicines before they are authorized for marketing.

They also have a similar structure when reviewing pharmaceutical product dossiers, but the

position of each milestone in the review process differs from one state to another.

The first study in the GCC was initiated by Hashan (2005) to assess the regulatory environment

in the six GCC states (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and UAE) using

comparative data on a country and regional level, in order to identify the key issues for

improving regulatory practices and ensuring new medicines were available in an efficient and

timely manner. The second study by Al-Essa (2011) was to map the key milestones and

associated activities for each agency in the GCC region and to determine the quality measures

employed by the agencies in their different procedures. Figures 4.1- 4.7 illustrate the process

maps for each of the countries participating in this study as well as the characteristics of the

process.

This part describes the comparison between the regulatory review processes in the seven GCC

regulatory authorities.

Validation process

The validation process is the first contact between the sponsors and the regulatory authorities.

Validation is an important checking point to ensure the correctness and completeness of the

submitted data before entering the scientific assessment stage. The seven authorities record the

date of receiving the registration dossier and carrying out a validation process to ensure that the

documents submitted for registration are complete before they can be accepted for review. After

examining the validation process, a considerable difference was observed in the time taken to

validate the registration dossier from one country to another, with Oman performing the

validation process immediately after submission while Bahrain takes 14 days to complete it.

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Figure 4.1 PROCESS MAP FOR BAHRAIN

73

Figure 4.2 PROCESS MAP FOR KUWAIT

74

Figure 4.3 PROCESS MAP FOR OMAN

75

Figure 4.4 PROCESS MAP FOR QATAR

76

Figure 4.5 PROCESS MAP FOR KINGDOM OF SAUDI ARABIA

77

Figure 4.6 PROCESS MAP FOR UNITED ARAB EMIRATES

78

Figure 4.7 PROCESS MAP FOR YEMEN

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Table 4.1 Models of assessment and characteristics in the Gulf States

Type of review model

Bahrain Kuwait Oman Qatar Saudi Arabia

UAE Yemen

Verification review

x x x x

Abridged review x x x Full review x x x x x

Number of reviewers

7 15 22 3 40 12 10

Validation time (days)

14 7 1 NA 10 1 NA

Queuing time (calendar days)

14-56 14-56 14-56 60-90 NA NAS: 60-180 EAS:180-365

NA

Scientific assessment (calendar days)

NA NA 90 NA 180-245 NA NA

Positive scientific opinion to final approval (calendar days)

30- 90 30 30 30 -90 30 30 to 90 180

Overall approval time (calendar days)

NA 180 120 NA EAS: 165 NAS: 290

NA 180- 365

*NA= Not Applicable

Queuing stage

The queuing process is straightforward and allows appropriate handling of the received

registration dossiers in an organized fashion. However, the lack of regular monitoring of queue

time could lead to a backlog. The queuing time varies considerably across the Gulf region

ranging from 14 days to over 365 days. For a medicine to remain in this stage for three months

unjustifiably delays patients‟ access to medicines.

Scientific review Phase

The scientific assessment stage is the major part of the regulatory review process where the

product quality, safety and efficacy dossiers are thoroughly evaluated. The starting date of the

scientific assessment is generally recorded in most of the GCC States, except in UAE and Qatar,

probably because the review process starts from the date of submission and ends at the date of

granting the approval. Five regulatory authorities in the Gulf region have scientific committees

as part of the scientific assessment process. Kuwait and Qatar do not have scientific committees

and the quality of the review report depends on the assessors‟ experience and skills in evaluating

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the registration dossier. The scientific assessment is not a target time in five GCC authorities

while Oman and Saudi Arabia specified a time limit of 90 days and 180 to 245 days respectively.

Queries to companies

In this phase all the communications occur between the sponsor and the authority with regards to

the registration of a new medicine in each GCC State. Questions and queries arising during the

scientific assessment and quality control analysis stages are collected into a single batch to be

sent to the sponsor by each of the seven GCC authorities. The sponsor‟s response time varies

significantly between the seven GCC States with the shortest time limit being 30 days enforced

by the Saudi Food and Drug Authority (SFDA) and the longest is approximately 365 days in

Qatar. The clock-stop concept is perceived differently across the region. In Kuwait, for example,

the authority does not enforce a limit for the sponsor‟s response time but if the sponsor fails to

respond in two years, the authority ceases the registration process and returns the dossiers to the

local agent and a new application is officially requested should the sponsor be still considering

the product registration in Kuwait Bahrain and UAE, however, do not have a clock-stop system

but they target a specified limit for the sponsors response time.

Overall target time for registration

While Bahrain Qatar and UAE were not setting a target approval time, the other four authorities

have slight differences in their overall target approval times with the shortest one in Oman being

120 days.

Part 2: Total number of product approved in each Gulf states, median approval times for

the Gulf States by year 2008-2010 and the median approval times for the different

pharmaceutical companies

In this study, three major areas were examined, for the period 2008-2010 namely, (1) Trends in

submission and registration of new pharmaceutical products; (2) Changes in the approval

timelines; (3) Approval times for Gulf, Arab non-Gulf, Asian and International pharmaceutical

products in the GCC States. The number of approved products in any regulatory authority is

affected by many factors. For example, the number of dossiers submitted to the authority and the

number of reviewers in the review section (Hashan, 2005). The GCC States are no exception and

like many other authorities the number of approved products varies from year to year influenced

by these and other factors.

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Total number of products approved in each Gulf state

In general, the countries reviewed a similar number of products, but there was an increase in the

number of approved products in 2010 in most GCC States compared to 2008 and 2009 with the

exception of Saudi Arabia (Table 4.2). This may reflect an increased interest by the industry in

the Gulf market or the authorities in the region were able to cope with an increased work load,

translating into an increased number of products approved. The GCC regulatory authorities share

common regulatory review practices that are critical in the establishment of a standardized

review process for the GCC region. The differences identified in the five review processes were

mainly due to the order of the steps carried out or the time spent in carrying out a certain

procedure. As per Al-Essa (2011) the approval timelines in the GCC States depend on the type of

products being registered, the quality of the submitted data and the level of interaction between

the sponsor and the authority.

In 2010, Kuwait registered the highest number of products among all the GCC countries with a

total of 210 products registered which is almost twice that of Saudi Arabia (92 products) (Table

4.2). Bahrain had the lowest number of products registered in total for 2008, 2009 and 2010 at

87, 149 and 174 products respectively. The analysis for each country is provided in the following

paragraphs. Oman is the only country in the GCC with a more or less constant number of

products registered between 2008 to 2010. Bahrain saw a steady rise in the number of registered

medicines from 87 approved products in 2008, 149 in 2009 and 174 in 2010 (Figure 4.8). This

steady increase in the registration of medicines in Bahrain was due to the decision from the

Ministry of Health (MOH) in Bahrain to facilitate the procedures for the drug registration if the

product is approved by advanced regulatory authorities such as EMA and USFDA or by one of

the reference countries in the Gulf.

Kuwait, on the other hand, saw a decrease in the number of registered medicines in 2009 and

2010 of 198 and 210 respectively as compared to 416 in 2008. According to the Kuwait

regulatory authority, the high number of approvals in 2008 was attributed to the pending files

with minimum requirement which were finalised in 2008, Hence, an increase in total number of

registered products in that year.

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Table 4.2 Number of approved products for Gulf Cooperation Council

(GCC) States in 2008, 2009 and 2010

Countries Type of company 2008 2009 2010

Approved

products

Approved

products

Approved products

Bahrain

Gulf 5 5 51

Arab non-gulf 25 37 42

Asian 7 2 19

International 50 105 62

Total 87 149 174

Kuwait

Gulf 81 51 43

Arab non-gulf 94 38 46

Asian 17 3 5

International 224 106 116

Total 416 198 210

Oman

Gulf 52 37 56

Arab non-gulf 15 25 29

Asian 15 5 12

International 89 105 81

Total 171 172 178

Qatar

Gulf 56 57 134

Arab non-gulf 39 13 11

Asian 1 0 0

International 107 30 62

Total 203 100 207

Saudi

Arabia

Gulf 150 91 16

Arab non-gulf 25 52 19

Asian 0 0 0

International 134 132 57

Total 309 275 92

In Saudi Arabia, the decrease in the number of registered medicines in 2010 as compared to

2008 and 2009 was attributed to the transfer of the tasks from the Ministry of Health to the

Saudi Food and Drug Administration in July 2010. During the transition period, the ministry

refrained from accepting new registrations until the transfer was completed, hence the

decline in the number of products registered. In Qatar, the decrease in the number of

registered medicines in 2009 as compared with 2008 and 2010 was attributed to the limited

number of registration committee meetings in 2009. Since the number of meetings was

reduced, the number of products registered was also affected.

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Figure 4.8 Number of approved products by the five regulatory authorities

(2008-2010)

Approval times in Gulf States

There are differences in the milestones within the approval process among the GCC States.

For example, the analysis step starts with the scientific assessment in Oman, Saudi Arabia,

and Qatar (parallel procedure), but in Kuwait and Bahrain the analytical step comes after the

scientific assessment (sequential procedure) and this could negatively impact the approval

time. The GCC authorities also waive the analytical stage for products registered in Kuwait,

Saudi Arabia, Oman, the GCC central drug registration (GCC-DR), and/or in countries with

advanced regulatory systems such as the United States Food and Drug Administration or the

European Medicines Agency (EMA).

The median approval time for all approved products in the GCC States ranged from 69 days

in Oman and Qatar in 2010, to 587 days in Saudi Arabia in 2008 (Figure 4.9). The Saudi

Arabia median approval time was two to three times the regulatory approval time in other

GCC States. This may be attributable to some products remaining in the approval process for

a longer time, or because some steps in the regulatory approval required more time to

complete or because they carry out a full review. However, upon verification with the Saudi

Arabia authority, the decrease in registration period for the three years (from 587 Day in

2008, 515 in 2009 and 439 day in 2010) was due mainly to the decrease in the number of

registration applications received by the MOH. With fewer files, the evaluation process and

decision-making were carried out in a timely manner.

84

Figure 4.9 Median approval times for all products (2008-2010)

Bahrain, recorded a decline in the registration period between 2008 and 2010. This decline in

the registration period in the year 2010 (from 264 days in 2008 to 166 days in 2010) was

attributed to the increase in the number of registration committee meetings and the increased

number of reviewers. This expedited the approval process and reduced the registration

process by 98 days.

Qatar also experienced a decrease in the registration period for the three years; 143 days in

2008, 87 Days in 2009 and 69 days in 2010. This was attributed to the increased number of

reviewers, hence expediting the approval process. By taking into account products that had

been approved by regulatory authorities in advanced countries such as the EMA and

USFDA, the local approval process becomes more streamlined and shortened. Kuwait

recorded a decline in the registration period for the same three years ranging from 346 days

in 2008 to 300 days in 2010. Oman also recorded a decline in the median approval time from

143 days in 2008 to 69 in 2010. The increase in the approval time in 2008 was due to the

development of the new regulations for approval of health and alternative products. These

new regulations created an overload for the Quality Control Laboratory, increasing the time

for the analysis of Pharmaceutical products.

Approval time for Gulf, Arab non-Gulf, Asian and International pharmaceutical

products in the GCC States

The approval times in the Gulf States varied based on the geographical location of the

manufacturer. For local companies it is easier to contact the authority and faster to reply to

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questions asked by the authority. International company products need a longer time for

approval for many reasons, including priority given to local companies and cultural

influences. Therefore, the following four figures examine the difference in the approval time

for different types of companies in the GCC States.

Gulf companies products

The median approval time for the products from Gulf companies varied from about 70 days

in Oman and Qatar in 2008, 2009, 2010 to more than 600 days in Saudi Arabia. The longest

approval time was for Saudi Arabia at 609 days in 2008, as shown in (Figure 4.10). The

regulatory review process for medicines in Saudi Arabia is carried out in the newly

established autonomous “Saudi Food and Drug Authority” which commenced its activities in

2008. The review process in Saudi Arabia comprises thirteen steps which are critical to the

whole process (Al-Essa, 2012). As a result, the approval time decreased significantly over

the period of this study. The Saudi Arabia authority ascertained that the reduction in approval

time was partly due to fewer product registration applications received in 2008, 2009 and

2010 from the GCC companies as well as the rapid responses from these companies

regarding any clarifications. The improvement in the approval time in Oman and Qatar in

2010 was due to the positive effects of the Gulf Centralised Registration system. Qatar MOH

for example requested the Gulf companies to register their products in the GCC Centralised

system before they submit their products to the local procedure and this led to a reduction in

the time needed to register the products. In Bahrain, the increase in the number of reviewers

had a positive effect on approval times. But in Kuwait, the health authority thought the slight

increase in approval times in 2008 and 2010 was mainly attributable to the delays in the

companies‟ response to the authority‟s queries which affects the overall approval time.

Bahrain, on the other hand, recorded an increase in the duration of medicine registration from

Gulf pharmaceutical companies in 2008 (520 days), a decrease in duration recorded in 2010

and no registration of any products from Gulf companies in 2009.The decline in the

registration period in 2010 was due to the increase in number of the registration committee

meetings and in the number of reviewers. On verification, there were no specific reasons

recorded as to why there was no registration for any products from Gulf pharmaceutical

companies in 2009. One of the probable reasons might have been that the Bahraini market is

very small in size and hence not attractive for companies to register their products locally.

86

Figure 4.10 Median approval time for Gulf companies products (2008-2010)

Arab non-Gulf companies products

The median approval time varied from 91 days in Oman in 2008 to 567 days in Saudi Arabia

in 2010. The approval time for Arab non-Gulf products in Saudi Arabia was four times that

in the other GCC States (Figure 4.11). The increase in the median approval time to more than

560 days in 2009 and 2010, respectively, was due to an accumulated backlog for the

registration applications during the transition period for the newly established authority

SFDA. Furthermore, priority was also given to products from local and Gulf companies at

the expense of Arab non-Gulf companies. Saudi Arabia also cited that the slow responses

from Arab companies further delayed the approval process. In Kuwait, the median approval

time was 559, 437 and 450 days in 2008, 2009 and 2010 respectively and the increase in

2008 was mainly due to lack of follow-up from the company to submit more documents or

answer questions asked by the authority. The reduction by 90 days between 2008 and 2010

was mainly due to an increase in the number of reviewers in the registration section. The

approval time in Bahrain, Oman and Qatar varied from 90 days to 531 (Figure 4.11). Qatar

recorded a reduction in the duration of registration of medicines from Arab non-Gulf

pharmaceutical companies and the median approval time is more constant over the 3 year

period. This is attributed to an initiative by the Qatari MOH requesting the companies to

register their products in the GCC Centralised system before they submit their products to the

local system which led to the reduction in the approval time.

87

Figure 4.11 Median approval time for Arab non-Gulf companies products from

(2008-2010)

The increase in the approval time in Oman in 2009 and 2010 was mainly attributable to the

delays of the company responses to the authority queries which affects the overall approval

time. A significant drop in the registration timelines in Bahrain for the products from Arab

non-Gulf companies was due to the decision from the Ministry of Health (MOH) to facilitate

the procedures for drug registration for products approved by any reference authorities such

as USFDA, EMA or SFDA.

International companies products

The median approval time in 2008 for products submitted by International companies varied

from 143 days in Qatar to 587 days in Saudi Arabia (Figure 4.12). The approval time for

Saudi Arabia is two to three times that of the other countries, with 587, 473 and 434 days in

2008, 2009 and 2010, respectively, which may reflect the fact that they carry out a full

review. The mean fluctuated with an increase in 2008, mainly due to priority given to local

and Gulf companies, which had a negative effect on the approval time for International

company products. However, between 2009 and 2010, there was an increase in the median

approval time, mainly due to products remaining in the approval process for a longer time.

The median approval time for other GCC States varied from 70 days to 301 days, but it

decreased with 143, 110 and 96 days in 2008, 2009 and 2010 in Qatar, due to the fact that the

International companies submit complete dossiers. Furthermore, in Kuwait the reduced

approval time was mainly because the NASs do not enter the quality control analysis stage as

88

long as the sponsor has provided complete pharmaceutical documents to ensure that this

product is of the desired quality. EASs, however, are sent to the Quality Control laboratory

for sample analysis and take the companies some time to follow up the queries.

Figure 4.12 Median approval time for International companies’ products

(2008-2010)

In Bahrain, there was an increase in the duration of the registration time for medicines from

the Europe and the U.S. in the year 2009 (264 days) as compared to 164 days in 2008 and

127 days in 2010. The Bahraini authority stated that this was due to some changes in the

administration process which led to a delay in drug registrations in 2009. In Oman, there was

a decrease in the median approval time for products from International companies from 217

days in 2008 to 182 days in 2010. The reduction in approval time is due to the fact that more

products from the International companies had been registered in GCC Centralised system

which reduces the time needed to register the products locally.

Asian companies’ products

The median approval time for products submitted in 2008 by Asian companies varied from

127 days in Qatar to 864 days in Oman (Figure 4.13). Saudi Arabia did not register any

products from Asian companies during this period because these companies were unable to

fulfill some of the registration requirements such as their product must first be registered

with an advanced regulatory body such as EMA and USFDA. Similarly Qatar also did not

89

register any products from Asian companies in 2009 and 2010. Thus, only Oman, Kuwait

and Bahrain registered products from Asian countries during these periods.

Figure 4.13 Median approval time for Asian companies’ products (2008-2010)

Bahrain registered an increase in the timelines of registration for Asian pharmaceutical

companies in 2009 (664 days) as compared to 203 days in 2010. The Bahraini authority

stated that the increase was attributed to several reasons, for example the low demand for

Asian pharmaceutical products in Bahrain, the products were not registered with reference

authorities or the products did not fulfill all the registration requirements such as bio-

equivalence studies.

The approval time for Oman was 697, 864 and 216 days in 2008, 2009 and 2010,

respectively. The mean fluctuated with an increase in 2008 and 2009 mainly due to the

development of new regulations for the approval of health products and alternative medicines

and the delay in the company responses to the authority queries. While Oman and Bahrain

registered an increased in the median approval time for Asian companies, Kuwait recorded a

decline in 2009 from 380 days in 2008 to 181 days in 2009. The Kuwaiti authority stated that

this was due to the increased number of reviewers. However, in 2010 the approval time had

doubled from that in 2009.

91

DISCUSSION

The regulatory environment has changed in recent years, largely as a consequence of internal

reviews designed to increase the efficiency and quality of the approval process. At the same

time relationships have become more open both those between different national regulatory

authorities and those between industry and the agencies perhaps due to the impact of

restructuring and performance improvement initiatives.

In order to make a consistent, timely and high-quality review decision the drug registration

agency has to acquire the following key components in their quality assurance system: 1.

Standard operating procedures; 2. Guidelines for the reviewers‟; 3. Review templates; 4.

Training programs; and 5. Management review of individual files.

This study investigated the pattern of the total regulatory approval time in GCC States in

2008, 2009 and 2010 for pharmaceutical products from Gulf, Arab (non-Gulf), Asian and

International companies. It revealed that the shortest median approval time was for the

products from Gulf companies. In contrast, products submitted by Arab non-Gulf, Asian and

International companies had the longest median approval times. The median regulatory

approval time varied according to the geographical situation of the pharmaceutical

companies. Several factors led to an improvement in the median regulatory approval time in

the GCC States during the study period, such as the Gulf Central Registration which had a

positive impact on submissions from the Gulf companies.

1. Trends in the overall approval times in the Gulf States

The study data showed a downward trend in the median approval time for most of the GCC

States, during 2008 to 2010. However, the approval time for all approved products in the

GCC States during this period varied from about 60 days in Qatar and Oman (2009 and

2010), and to about 609 days in Saudi Arabia (2008).

There are many factors which can affect and explain the differences in approval time in the

GCC States. The main factor is the difference in the positions of milestones within the

approval process, for example, the analytical step starts with the scientific assessment in

Oman, Saudi Arabia, and Qatar (parallel procedure), but in Kuwait and Bahrain the

analytical step comes after the scientific assessment (sequential procedure). The study

91

identified the negative influence of the sequential procedure on the products approval times.

The speed and uniformity of the sample analysis can be achieved by fixing a time limit,

which may improve the handling of the analytical procedure along with the required quality

control tests in order to meet the target time. Furthermore, carrying out the quality control

analysis in parallel with, rather than after the scientific assessment, would be a rational

decision to avoid any impediment to patients‟ access to medicines.

Bahrain and Qatar do not specify target approval times as there are several factors involved

in their decisions. The major influencing factors are, the types of products being registered

(i.e. whether they are NASs, EASs, or therapeutically important or life saving products), the

quality of the submitted dossiers and the level of follow-up and interaction between the

pharmaceutical company and the authority. The other three authorities showed slight

differences in their overall target approval times with the shortest one in Oman being 120

days. Regulatory approval times have also been influenced by the type of assessment carried

out by different authorities. Bahrain and Kuwait conduct a verification reviews for all types

of products registered in countries with competent authorities. Saudi Arabia performs a full

review on all types of application while Oman and Qatar perform an abridged review for all

products. It must be noted that all the GCC regulatory authorities require the submission of

the Certificate of Pharmaceutical Product at one point during the registration process as this

is the most important requirement for successful completion of the approval process in the

five member states. The GCC states could take the Singapore system as an example to reduce

the overall approval time by conducting verification review for all types of medicines which

are previously authorized by at least two reference authorities, except for biological and

biotechnology products.

GCC states should seek to increase the level of funding to bring about the required expertise

and resources to conduct a more extensive review of important medicines, including

biological and biotechnology products. A clock stop is another important approach which is

not fully enforced in the GCC authorities to control the overall approval time. EMA is

obliged by the regulation to reach a decision within 210 days, although the clock is stopped if

it is necessary to ask the applicant for clarification or further supporting data (EMA, 2009).

In any case, the clock stop is an important practice that has several advantages for the review

process, namely,

1. It controls the approval time

92

2. It keeps the sponsor alert to the time limit and the consequences of delays of their

responses to the authority.

3. It improves the interaction and follow-up practices between the sponsor and the authority

4. It minimizes the backlog problem

2. The review times in the Gulf States

The review of new drug applications by regulatory agencies around the world is an

immensely complex process and the factors influencing regulatory behaviour are

numerous. According to the Centre for Drug Evaluation and Research (CDER) of FDA, the

staffing and disease politics (media coverage of diseases) play an important role in the drug

approval process. An appropriate number of staff has been the dominant influence on

review times for New Active Substances. It is essential to have a target time for the

scientific assessment and to monitor the assessment time in order to prevent delays that

may impact the final approval time. In the US FDA reviewers are under constant pressure

to meet time goals. They do not only review new drug applications (NDAs), but also other

key documents submitted by sponsors, some of which also have time goals attached. At the

same time, reviewers must provide advice to sponsors and stay abreast of the latest

scientific advances in their fields. The results of a study on the US FDA‟s review process

for NDAs, revealed that the allotted six months priority review and ten months standard

reviews were found to be inadequate due to concerns of time pressure on the FDA

reviewers which ultimately required the agency to hire close to an additional 300

employees within five years with funds from user fees (Rehnquist, 2003).

The main factors (Barrocliffes et al. 1994, Donnelly et al 1996) which may impact on

review times are the harmonisation of technical requirements, increase in dialogue between

industry and authorities, restructuring and reorganization of authorities, introduction by

authorities of user fees and target review times. This suggests that differences in review

times between competent authorities may be related to the way in which the review is

managed. The time taken from reaching a positive opinion by the scientific committee to

the final approval varies considerably across the region taking less than 30 days in Kuwait

and Oman and less than 90 days in Bahrain, Qatar and Saudi Arabia. This is the time

period to complete the final administrative procedures before granting the registration

approval in each country. It is important for the authorities to consider improving their

93

internal bureaucratic procedures that cause unnecessary delays in the authorization time

without any justifiable reason related to the quality of the submitted registration dossiers.

Most regulatory authorities have procedures for accelerated reviews like the fast track

procedure in Europe, based solely on potential gain time from conditional licensing or from

authorisation under exceptional circumstances. Hence the need for the product does not seem

to be a determinant of the speed of the review. The utilisation of abridged reviews, mutual

recognition and assessment review sharing among regulatory authorities may enhance the

efficiency of scientific reviews. Initiatives such as increased dialogue, production of early

guidelines and training of regulators may enable increased efficiency. The speed of review

may depend on the need for the product, the quality of the dossier and the efficiency of the

regulatory process. Still there is little evidence to show that the need for the product is a

determinant of the review speed or the time to bring the product to the market. Accelerated

reviews, fast track procedures and priority assessments constitute the efficiency of the

regulatory agency (Lumley et al 1996). Facilities for accelerating the development of certain

products for licensing under exceptional circumstances also are added measures in the

regulatory process. Sometimes a fast track procedure means that under certain very

specialized circumstances the regulatory authorities will assess a dossier ahead of time. The

criteria should be solely those of a significant potential gain for public health. Adherence to

strict time limits has been one of the quantitative measures for the success of a regulatory

authority. This has been achieved partly through the introduction of a pre-submission phase

and clear dialogue (sound scientific advice) with the applicant. Performance indicators like

the Application Tracking Systems (ATS), monthly publication of decision tables, quality

management systems, questionnaires, may accelerate the overall assessment and the drug

registration process in the GCC states.

3. The influence of the type of Companies on approval times

Analysis of the 2008 data showed that, the approval time for the products of Gulf companies

to be the shortest followed by Arab non-Gulf and International companies in most of the Gulf

countries. The main reason for this is the priority given to local manufacturers in the Gulf

States. In addition, the rapid responses from these companies also help to expedite the

approval processes. The local manufacturers have an unwritten priority in all regulatory

review processes, as a part of governmental support to encourage local industry. Such

94

priority treatment reflects positively on approval times. The approval time for products from

the Gulf companies was the shortest, compared to other types of companies. The median

approval time in some authorities in 2010 was similar e.g. in Qatar there was no significant

difference between types of companies nevertheless the approval time for local products still

showed continuous improvement during 2008, 2009 and 2010 at 102 days, 86 days and 69

days, respectively. The longest approval time was for products from Asian countries in Oman

which was 864 days in 2009 and 395 days in Kuwait in 2010. An unwritten review priority

has always been given not only to products from the Gulf companies but also to products

indicated for serious, life-threatening conditions in the GCC states. This is in line with the

Canadian priority review for medicines and medical device applications intended for the

treatment, prevention or diagnosis of serious, life threatening or severely debilitating

illnesses or conditions. Their priority review is specifically applicable where no product is

currently marketed in Canada and/or where a new product represents a significant increase in

efficacy and/or significant decrease in risk such that the overall benefit-risk profile is better

than that of existing therapies (Canadian Review process, 2006). The longer approval time

for the products from local companies in Saudi Arabia, compared to other GCC States, may

be due to the sequential approval process followed in Saudi Arabia. However, the median

approval time for products from Gulf companies in 2010 in Oman was about 79 days and

Qatar it was 70. These shorter approval times may be due to the parallel approval procedure

used in Oman and Qatar. It is important to note that the scientific assessments in Saudi

Arabia are carried out by independent specialist academic staff which could lead to more

difficult questions and consequently require more time to respond on the part of

pharmaceutical companies, while in the other GCC States, the scientific assessments are

carried out by internal pharmacists.

In addition to the priority procedure, there are many other factors which affect the approval

time of local companies positively, like the ease of establishing contact with key individuals

in the authority and a rapid response to queries raised by the authority. Overall the median

approval time is reduced radically for all products from all regions. The main reasons for

this decrease in approval time between 2008 and 2010 in the Gulf States are due to the

positive effect of the Gulf Central Registration, a rise in the number of reviewers in some

GCC drug authorities and the parallel procedure used in the regulatory approval review

process.

95

SUMMARY

The findings from this study showed a downward trend in the median approval time

for most of the GCC States between 2008 and 2010.

The main reasons for the decrease in approval time in the Gulf States are due to the

positive effect of the Gulf Central Registration, the rise in the number of reviewers in

some GCC drug authorities and the parallel procedure used in the regulatory approval

review process.

Regulatory approval times in the GCC states have been influenced by the type of

assessment carried out by different authorities.

Clock stop is not fully enforced in the GCC authorities to control the overall approval

time.

The GCC states should seek to increase the level of funding to bring about the

required expertise and resources to conduct a more extensive review of important

medicines, biological and biotechnology products.

Performance indicators such as Application Tracking Systems, monthly publication

of decisions and quality management systems, may accelerate the overall assessment

and drug registration process in the GCC states.

96

CHAPTER 5

An Evaluation of the GCC Centralised

Regulatory Review Process

97

INTRODUCTION

The approval of medicines in different countries across the world has been and still is

performed by regulatory agencies according to their national regulations, although, attempts

to harmonise the regulations have been made for several years within the GCC region. The

harmonisation of the regulatory review processes in the GCC States was initiated following

the issuance of the GCC Health Ministers‟ Council Decree No. 8 in 1976 regarding the

formation of a study group to report on how a centralised registration review system should

be established to monitor the marketing of medicines and develop common guidelines for the

participating authorities (Al-Essa, 2011).

This was followed by a series of GCC Ministerial Decrees relating to the establishment of a

centralised registration system which was not approved until the Kingdom of Bahrain

submitted a proposal for the formation of a “Central Committee for the Gulf States” to

register pharmaceutical companies and their products. This committee ensures that the

pharmaceutical companies apply satisfactory standards to guarantee manufacturing of high

quality, safe and effective medicines and to standardise their regulations with regards to

medicines importation practices in the Gulf States.

The Centralised Procedure for the registration of pharmaceutical companies and medicinal

products has been established under the Executive Board of the Health Ministers Council for

GCC States. The Executive Board is chaired by the Director General, who is responsible for

supervising the work of the board and following up the resolutions and recommendations of

the Health Ministers‟ Council, assisted by technical, administrative and financial

departments.

The Gulf Centralised Committee for Drug Registration (GCC-DR) was formed in May 1999

and included Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, the United Arab Emirates with

Yemen (joining in 2003). The GCC-DR consists of two representatives from each member

state. The main role of the committee is to register pharmaceutical companies and their

products through the joint coordination of the safety, efficacy and quality of medicinal

products.

98

In order to adopt the Central Registration System, the following two phases were proposed.

Phase 1: In the year 2000, pharmaceutical companies in the Gulf States had to register their

products using the local national system while at the same time it was mandated that they

also use the centralised system. During a period of two years the following was required:

The registration of research companies by the GCC-DR in accordance with the

centralised registration.

The registration of new chemical entities, biological and new technology products.

A priority was given to the Gulf States companies to register centrally.

The registration of products which have not been through the centralised procedure but

have been selected for the GCC international tender.

Phase II: The second phase took effect in 2002 following an evaluation of phase I and

during this phase all the companies could submit their products through the GCC procedure.

During the eleven years (1999-2010) the GCC centralised system received 1,824 medicinal

product applications and approved 1,165. This study has highlighted the different steps in the

review process in the GCC-DR system and the way in which these influenced the overall

timelines. Information was obtained to identify the practices that accelerate or delay the

marketing authorisation. Therefore this study mapped the key milestones and associated

activities and evaluated the quality measures employed by the GCC-DR process.

OBJECTIVES

The objectives of this study were to:

Appraise the regulatory review process in the GCC Central Registration operation.

Evaluate the review times for New Active Substances (NASs) and Existing Active

Substances (EASs) submitted to the GCC Centralised Registration (January 2006 to

December 2010).

Identify the strengths and weaknesses of the centralised review process.

Propose strategies that could help the GCC-DR enhance the drug review process

leading to improved patient access.

99

METHODS

Information on the total number of applications and approvals together with the timelines

from January 2006 to December 2010 were obtained directly from the Executive Board of

the Health Ministers Council for GCC States. The data included the application submission

date, the registration date and the overall review time. The products were classified into four

groups according to the location of the manufacturing companies (GCC, non-GCC Arab,

international and Asian). The data also included information on different dosage forms

(solids, semi-solids, liquids, injectables) and the therapeutic indications.

THE GULF CENTRALISED PROCEDURE REVIEW PROCESS MAP AND

MILESTONES

Currently the Executive Board is responsible for receiving the registration files and the

prescribed fee for the registration of pharmaceutical manufacturing companies and their

products. After receiving the files, the Executive Board forwards the files to all the member

states for their evaluation. Every member state should review the files and provide their

recommendations to the GCC-DR. The registration of the company is decided based on the

recommendation of the inspection team. If the company has been recommended to be

registered, the GCC-DR issues the registration certificate; otherwise the company will be

notified accordingly. The inspection team consists of three members from three different

member States. The selection of members is carried out based on certain criteria where every

member state would have an equal number of visits. Upon completion of the visit, the head

of the inspection team will prepare a visit report and it is signed by other members of the

team and then the report is submitted to the GCC-DR. Similarly, the GCC-DR forwards the

registration files of the products to each individual Member State for evaluation. The

samples are sent for analysis to one of the four laboratories (Saudi Arabia, UAE, Kuwait and

Oman) which are accredited by GCC-DR. The registration of products is determined on the

basis of the analysis reports. There are basically five steps for the regulatory authority in the

Gulf Central Registration System. Some of these steps are critical and constitute a substantial

part of the review process (Figure 5.1). The review process map indicates the main steps in

the review and approval process and identifies the key milestones for monitoring and

analysing timelines. Receipt and validation include administrative registration (reference

number) and checks on legal requirements, the status of the company, manufacturer etc. as

well as a „checklist‟ validation of the application content (e.g. technical sections, CPP status).

The pharmaceutical

111

Figure 5.1: PROCESS MAP FOR GCC CENTRALISED REGISTRATION

(A) RECEIPT OF APPLICATION BY EXECUTIVE BOARD

(B) ACCEPTED FOR REVIEW

(C) SCIENTIFIC REVIEW STARTS

(D) START OF GCC-DR PROCEDURE

(E) QUESTIONS TO COMPANY REGISTRATION REJECTION

Receipt & Validation Procedures Validation Time

7-10 days

Queuing for review Administration Time

1-2 weeks

Safety Efficacy Sample analysis

Registration Dept. in GCC Countries Quality Control Laboratory

<<< Parallel review, >>>

Questions processed by Company

Reply from Company

GCC-DR

REGISTRATION

Quality

<<2 Months>> <<4-5 months>>

Meets every 3 months

Registration Certificate

Overall registratio

n tim

e 6

-8 m

on

ths

111

companies are required to submit 16 samples of their product in addition to eight copies of

the product dossier and one original copy which would remain with the Gulf Central

Registration Office. While two separate GCC States would be chosen through a computer

program alphabetically according to the countries name, to act as rapporteurs, the other GCC

States would keep the dossiers for documentation purposes. The rapporteurs are not chosen

because of their expertise in a certain area of regulatory science, but to give equal

opportunities to all the members states in a systematic manner of selection. Similarly, the

reference laboratory chosen, to carry out the analysis, is based on the equity of the number of

dossiers distributed between these laboratories and not on the ability of these laboratories to

perform the analysis.

Hypotheses

This study examined the following hypotheses,

1. There was a significant increase in the number of products registered from 2006-

2010.

2. The highest number of products approved by GCC-DR is linked to those originating

from the companies in the GCC region.

3. There was a significant increase in the approval time between 2006-2010 in the GCC-

DR.

4. The approval time for products from GCC pharmaceutical companies was shorter

than for other companies.

RESULTS

Products considered and their characteristics

During the five year period (2006 - 2010), the number of pharmaceutical products for human

use successfully registered through the GCC Centralised Registration procedure was 413. For

the purpose of clarity the results will be presented in four parts as follows:

Part I - Number of products approved in the Gulf Centralised Procedure.

Part II - Approval time in the Gulf Centralised Procedure.

Part III - Approval time for different dosage forms

Part IV - Approval time for different therapeutic groups.

112

Part I: Number of products approved in the Gulf Centralised Procedure

(2006 - 2010)

A total of 413 Pharmaceutical Products (EASs and NASs) were registered by GCC-DR

during the time period 2006-2010. The highest number was found in the year 2009 (130;

32%) followed by the years 2007 (116; 28%), 2008 (91; 22%) and 2006 (60; 15%) (Figure

5.2). There was a substantial drop in the number of approved products in 2010 (16;4%)

which was due to the fact that the pharmaceutical companies failed to comply with the new

GCC guidelines for the stability testing of active pharmaceutical ingredients (APIs) and

finished pharmaceutical products (FPPs). The GCC countries come under climatic Zone III

and IVa (hot and dry & hot and humid) the new guideline which was implemented in 2009

replaced the long-term testing condition of 25 °C ± 2 °C/60% RH ± 5% RH for climatic

zone III and IV with 30 °C ± 2 °C/65% RH ± 5% RH. The results showed an overall

significant association (p<0.001) between the total number of registered pharmaceutical

products and registration years.

Approval of Existing Active Substances (EASs) and New Active Substances (NASs) in

the Gulf Centralised Procedure (2006 – 2010)

Out of the total of 413 products approved in the Gulf Central Registration between 2006 and

2010, 317 products were EASs (Table 5.1) and 96 NASs (Table 5.2).

Figure 5.2: Total number of pharmaceutical products approved in the Gulf

Centralised Procedure (2006-2010)

Statistical analysis of these data using a simple linear regression showed a significant association between the

total number of registered pharmaceutical products and registration years (p<0.001).

0

20

40

60

80

100

120

140

2006 2007 2008 2009 2010

Num

ber o

f Pro

duct

s

Registration Year

Line of best fit

Major

regulatory

change:

implementati

on of ICH

stability

113

Table 5.1: Number of EASs Approved in the Gulf Centralised Procedure from various

regions, dosage forms and therapeutic classes

Characteristics Registration Year

2006 2007 2008 2009 2010

Region Number of EASs Total

Arab 7 9 12 20 3 51

Asian 6 2 7 3 0 18

Gulf 38 64 46 46 12 206

International 5 10 11 16 0 42

Dosage Form

Injectables 16 4 14 9 0 43

Liquids 6 18 15 22 3 64

Semi-Solids 9 15 13 6 1 44

Solids 25 48 34 48 11 166

Therapeutic Class

Anaesthesia 2 0 0 1 0 3

Cardiovascular system 14 8 20 15 1 58

Central Nervous system 4 8 9 9 3 33

Ear, Nose and Oropharynx 0 1 0 0 0 1

Endocrine system 2 2 0 17 3 24

Eye 0 1 1 3 0 5

Gastrointestinal system 4 6 3 3 1 17

Immunological Products and Vaccines 0 0 0 0 0

0

Anti-infective 10 28 26 19 3 86

Musculoskeletal and Joint diseases 6 6 3 4 0 19

Malignant disease and immunosuppression 0 0 0 0 0 0

Nutrition and Blood 7 5 3 3 0 18

Obstetrics, Gynaecology and Urinary-tract

disorders 0 0 0 1 2

3

Respiratory system 3 8 7 6 2 26

Skin 4 12 4 4 0 24

Total 56 85 76 85 15

114

Table 5.2: Number of NASs Approved in the Gulf Centralised Procedure from various

regions, dosage forms and therapeutic classes

Characteristics Registration Year

2006 2007 2008 2009 2010

Region Number of NASs Total

Arab 0 0 0 0 0 0

Asian 0 0 0 1 0 1

Gulf 0 2 0 0 0 2

International 4 29 15 44 1 93

Dosage Form

Injectables 2 21 9 26 1 59

Liquids 1 2 0 2 0 5

Semi-Solids 0 0 0 0 0 0

Solids 1 8 6 17 0 32

Therapeutic Class

Anaesthesia 1 0 1 0 0 2

Cardiovascular system 0 6 7 11 0 24

Central Nervous system 0 1 2 2 0 5

Ear, Nose and Oropharynx 0 0 0 0 0 0

Endocrine system 1 3 0 10 0 14

Eye 0 1 0 0 0 1

Gastrointestinal system 0 1 1 0 0 2

Immunological Products and Vaccines 0 0 0 13 0 13

Anti-infective 0 0 0 2 0 2

Malignant disease and immunosuppression 0 2 3 0 0 5

Musculoskeletal and Joint diseases 0 0 0 1 0 1

Nutrition and Blood 2 17 1 4 0 24

Obstetrics, Gynaecology and Urinary-tract

disorders 0 0 0 1 1

2

Respiratory system 0 0 0 1 0 1

Skin 0 0 0 0 0 0

Total 4 31 15 45 1

115

There were a similar number of EASs approved centrally in 2007 and 2009 (85; 27%)

followed by 2008 (76; 24%), 2006 (56; 18%) and 2010 (15; 5%) (Figure5.3). Statistical

analysis using a simple linear regression analysis showed that the increase in the number of

registered EASs was statistically significant (p<0.001).

The highest number of NASs was registered in 2009 (45), whilst the lowest was in 2010 (1)

(Figure 5.4). Out of the 96 NASs, 93 products (97%) were found to be from international

companies. Statistical analysis using a simple linear regression showed a significant increase

in the number of registered NASs (p<0.001).

By individual regions, 208 (50%) medicines were identified as being approved from Gulf, 51

(12%) from Arab non-GCC, 19 (5%) from Asian and 135 (33%) from international

companies (Figure 5.5). Out of the total of 317 EASs approved in the Gulf Central

Registration between 2006 and 2010, by individual regions, 206 (65%) drugs were identified

as being approved from Gulf, 51 (16%) from Arab non-GCC, 18 (6%) from Asian and 42

(13%) from international companies.

Figure 5.3: Number of EASs approved in the Gulf Centralised Procedure

(2006-2010)

Statistical analysis using a simple linear regression showed a significant increase in the number of registered

EASs (p<0.001).

0

20

40

60

80

100

Num

ber o

f Pro

duct

s

Rigistration Year

Line of best fit

Major regulatory

change:

implementation

of ICH stability

guideline

116

Figure 5.4: Number of NASs approved in the Gulf Centralised Procedure

(2006-2010)

Statistical analysis using a simple linear regression showed a significant increase in the number of registered

NASs (p<0.001).

Figure 5.5: Approved pharmaceutical products (EASs & NASs) from GCC international, Arab

non-GCC and Asian companies (2006-2010)

0

50

100

150

200

250

Gulf International Arab Asian

Nu

mb

er

of

Pro

du

cts

Company type

New Active Substances Existing Active Substances

117

Part II: Approval times in the Gulf Centralised Procedure (2006 – 2010)

The total approval time for the period studied (2006 - 2010) includes all the 413 EASs and

NASs from different companies. During the five years, the median approval time ranged

from 107 days in 2006 to 265 days in 2010. There was a significant increase in the median

approval time between 2006 and 2010 which was due to several factors. These included the

limited number of meetings by the GCC-DR. although the seven member states met four to

five times a year to discuss the product review reports, on the other hand there was a steady

increase in the number of registration applications. Another reason for the delay in

registration was the assessment review process where two authorities are selected

alphabetically to review a registration dossier. There was also a lack of a standard evaluation

template for product assessment which leads to an increase in the correspondence which is

sent to the sponsor in several batches and at different times. Statistical analysis using the non

parametric test (Kruskal-Wallis test) across the five-year period showed that there was a

significant increase in the approval time for pharmaceutical products (p<0.001) (Figure 5.6)

Figure 5.6: Median approval time for all pharmaceutical products in the Gulf

Centralised Procedure (2006-2010)

0

50

100

150

200

250

300

2006 2007 2008 2009 2010

App

rova

l Tim

e(Ca

lend

er d

ays)

Registration Year

Line of best fit

Statistical analysis using non parametric test (Kruskal-Wallis test) over the five-year period showed that there

was a significant increase in the approval times for pharmaceutical products (p<0.001).

118

Approval time of Existing Active Substances (EASs) in the Gulf Centralised Procedure

(2006 - 2010)

Approval time for the 317 EASs approved in the Gulf Centralised Procedure between 2006

and 2010 varied from one year to the next. The lowest median approval time was for 2006

(114 days) and the highest median for 2010 (265 days) (Figure 5.7). Statistical analysis using

the non parametric test (Kruskal-Wallis test) across the five-year period showed that there

was a significant upward trend in the median approval time for EASs (p<0.05). In general for

the years 2006 to 2009 there is a wide range because in the centalised procedure there is no

defined target time within which the company time is also not specified (no clock stop).

However, in 2010 the range is significantly reduced because there were very few products

approved as a result of the implementation of ICH stability guideline.

Figure 5.7: Median approval time for EASs in the Gulf Centralised Procedure

(2006-2010)

Statistical analysis using the non parametric test (Kruskal-Wallis test) over the five-year period showed that

there was a significant difference in the median approval time for EASs (p<0.05)

Approval time for Existing Active Substances (EASs) by GCC, international, Arab non-

GCC and Asian companies (2006-2010)

The median approval time for EASs varied for different cohorts of companies based on

location, for example the shortest approval time was for Gulf company products (134 days)

and the longest for those of international companies (346 days). The shortest approval time

119

for Gulf company products was due to the waiver of analysis requirements. A product is

waived from analysis if it is registered in any one of the 4 GCC countries (Oman, Saudi

Arabia, United Arab Emirates or Kuwait) where the Quality Control Laboratory for these

States has the accreditation from the GCC. The median approval time for Arab companies

was 227 and 332 calendar days for Asian companies. Statistical analysis using the non

parametric test (Mann-Whitney U test) showed that there was a significant difference of

approval time between international companies (median approval time=346 days ) and Gulf

companies (median approval time=134 days) (p<0.001).

Approval time for New Active Substances (NASs) in the Gulf Centralised Procedure

(2006 - 2010)

In the year 2009, the highest number of NASs was registered (45 products) with a median of

288 days. In 2006, only four products were registered with median of 31 days. In 2007, 31

NASs were registered with a median of 138 days. In 2008, 15 products were registered with

median of 140 days. In 2010, the lowest number of products was registered (1 product only)

with a registration time of 131 days. The results obtained from performing analysis of

Kruskal-Wallis test showed that there was a highly significant upward trend in the median

approval time for NASs products between 2006 and 2010 (p<0.001). This was due to several

factors, including a limited number of meetings by the GCC-DR (only four to five times a

year) and during this period there was a steady increase in the number of registration

applications (Figure 5.8). The reason for the variation in approval times is similar to that

expressed for EASs. This variation is not acceptable and could be mitigated by introducing

target times.

Part III: Approval time for different dosage forms for all Existing Active

Substances (EASs) and New Active Substances (NASs) in the Gulf

Centralised Procedure (2006-2010)

From the 317 EASs registered with the Gulf Centralised Procedure between 2006-2010, the

lowest number constituted the injectable forms (14%) followed by the semi-solid dosage

forms ( 20% ) with the highest represented by solid dosage forms (52%). Approval times

111

Figure 5.8: Median approval time for NASs in the Gulf Centralised Procedure

(2006-2010)

Statistical analysis using the non parametric test (Kruskal-Wallis test) showed that there was a significant

difference in the median approval time for NASs between 2006 and 2010 (p<0.001).

ranged from 138 days for liquids to 350 days for injectables (Figure 5.9). In general, when

the dosage form is more complex, additional time is needed to approve the product. Special

studies and more steps are needed to analyse some products such as solutions for IV infusion

which need additional tests such as sterility and pyrogen testing.

Figure 5.9: Median approval time for different dosage forms for EASs and NASs in the Gulf

Centralised Procedure (2006-2010)

0

50

100

150

200

250

300

350

400

Injectables Liquids Solid Semi solid

App

rova

l Tim

e(D

ays)

Dosage Form

Existing Active Substances New Active Substances

111

In terms of dosage forms, out of the 96 NASs registered in the Gulf Centralised Procedure

(2006-2010), the lowest number registered was represented by the liquid dosage forms (5)

with a median approval time 128 days. The highest number registered was represented by the

injectable forms (59) with a median approval time 288 days.

Part IV: Approval times for Existing Active Substances (EASs) and New

Active Substances (NASs) by therapeutic class, (2006-2010)

The therapeutic class of 314 EASs was assessed and the lowest number was represented by

ear, nose and oropharynx preparations (1 preparation) and the highest number represented by

anti-Infective (86 preparations). The analysis of the approval time of EASs registered

between 2006 and 2010 involved the four largest therapeutic groups, namely,

The cardiovascular system (CVS)

The central nervous system (CNS)

The gastro-intestinal system

Anti-infective

The range of approval times for EASs analysed by therapeutic class varied from 206 days for

central nervous system products to 162 for anti-infective products (Figure 5.10). The trend in

approval times for EASs from different therapeutic groups was attributed to the GCC-DR

assessment requirements depending on the nature of the products which may include the

need for both clinical and bioequivalent studies and the prolongation of the analytical time.

Ninety-six NASs were approved between 2006-2010 and the lowest number was represented

by the eye, musculoskeletal and joint disease and respiratory system preparations (one

preparation) whereas, the highest number was represented by cardiovascular and nutrition

and blood preparations (24 preparations). The median approval times for NASs analysed by

the main therapeutic classes ranged from 274 days for anti-infective products to 92 for

gastro-intestinal products. The main factor for the variation in the approval time for different

therapeutic groups was the nature of the products evaluated.

112

Figure 5.10: Median approval time for different therapeutic class for EASs and NASs in the

Gulf Centralised Procedure (2006-2010)

DISCUSSION

This study investigated the pattern of total regulatory approval times in the Gulf Centralised

Procedure over the period from 2006 to 2010. It also addressed the various factors which

may have a positive or negative effect on the total approval times. It showed that the total

number approved in the Gulf Centralised Procedure was 413 including both Existing Active

Substances (EASs) and New Active Substances (NASs). The outcomes revealed that the

largest number of medicines submitted for review and approved by GCC-DR occurred in

2009. The study examined four hypotheses and their respective findings are discussed below.

Hypothesis 1: There was a significant increase in the number of products registered

from 2006 to 2010.

The highest percentage of approved products was in the year 2009. There was a considerable

decrease in the number of approved products in 2010. This was due to the fact that the

pharmaceutical companies failed to comply with the new GCC guideline for stability testing

of active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs).

The new guideline was a major challenge to most of the pharmaceutical companies leading to

the rejection of those which failed to meet the new stability study specifications. Other

factors influencing the number of approved products in 2010 were that the Saudi FDA began

to evaluate all the products in addition to the two rapporteurs from the Gulf States designated

0

50

100

150

200

250

300

Cardiovascular system

Central Nervous system

Gastrointestinal system

Anti-infective

Appr

oval

Tim

e (D

ays)

Therapeutic Class

Existing Active Substances(EASs) New Active Substances (NASs)

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to review the products. This resulted in a large number of queries raised from the Saudi Food

and Drug administration (SFDA) which substantially delayed the review process and there

was a significant decrease in the number of products approved in 2010. However, despite this

change in 2010, this hypothesis was accepted.

Hypothesis 2: The highest number of products approved by GCC-DR is linked to those

originating from the companies in the GCC region.

The number of products approved during the period of the study varied for different

companies based on their geographical location. The highest percentage of products

approved was from the Gulf companies, followed by Arab companies, international

companies and finally the Asian companies. However, the highest number of products

approved from GCC companies could be due to several factors including; that the GCC

manufacturers increased their efforts to obtain the GCC-DR approval in order to facilitate

entry into the international tender which is the common purchase route by GCC states. This

has an impact on the number of submissions and approvals in GCC-DR. Other factors that

might have also contributed to the increased number of products approved by GCC-DR from

GCC companies was the decision to waive the requirement to submit full time stability

studies during the first submission. The GCC manufacturers need to submit only one year

full time stability data during the first submission. However, non-GCC manufacturing

companies need to submit full time stability studies for the whole shelf life. This is because

the GCC States are making efforts to support and improve their local manufacturing

capabilities and the production capacity for the local population. The lower number of

products approved by GCC-DR was from non-GCC manufacturing companies due to the

strict GCC regulations that require evidence of registration in countries with developed

regulatory systems. Therefore this hypothesis was accepted.

Hypothesis 3: There was a significant increase in the approval time between 2006-2010

in the GCC-DR.

During the five year period of the study (2006 – 2010), the median approval time

significantly increased due to several factors which included the limited number of meetings

by the GCC-DR and the increased number of applications for registration. Other factors that

delayed the registration were the assessment review process where two authorities are

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selected alphabetically to review the registration dossier. In addition, the lack of a standard

evaluation template for product assessment leads to an increase in the correspondence which

is sent to the sponsor in several batches and at different times. It is recommended to have one

standard assessment template and rather than selecting the reviewing authorities

alphabetically, the dossier should be sent to all countries and all assessments combined into

one final report on which the final decision in the GCC-DR could be based. A clock-stop

system is not enforced in the Gulf Centralised Procedure and this delays the company

response to queries from the GCC Central registration committee. The implementation of a

clock-stop will ensure the sponsor meets the deadline and would allow more time for the

reviewers to complete the assessment of the submitted data. The sample analysis stage is an

essential part of the review process that impacts on the overall approval time. It is completed

after the scientific assessment as the outcome of the sample analysis affects the final approval

decision. Carrying out the quality control analysis in parallel, rather than after the scientific

assessment, would avoid the impact in the overall registration time. The queuing process is

straightforward and allows appropriate handling of the registration dossiers in an organised

manner. However, the lack of regular monitoring of queue time could lead to a backlog.

Managing the priority review is another important issue that needs recognition by GCC-DR

and should be dealt with according to set guidelines and SOPs that clearly specify the

conditions under which products can be taken out of the queue for such review. Therefore,

adequate resources and electronic handling of the queuing process should be provided to

support accurate follow-up of the pending dossiers, priority reviews and fast-track products.

On the basis of these finding this hypothesis has been accepted.

Hypothesis 4: The approval time for products from GCC pharmaceutical companies

was shorter than for other companies.

The approval time for pharmaceutical products varied for different cohorts of companies

based on their location, for example the shortest approval time was for the Gulf company

products and the longest for international companies and this was due to the waiver of

analysis requirement. The analysis is waived for a product if it is registered in any one of the

four GCC countries (Oman Saudi Arabia, United Arab Emirates or Kuwait) where the

Quality Control Laboratory has the accreditation from the GCC. There are other factors

which have a positive effect on the approval time for Gulf companies but have a negative

effect on the international, Arab non-GCC and Asian companies.

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This includes the geographical proximity of the company to the authority which leads to an

effective interaction and thus a faster response to any question asked by the authority.

Additionally, most locally manufactured products are EASs and do not need very much

consultation during the scientific review compared to NASs.

However, a priority procedure is a common practice in many authorities, the rapid approval

time is also due to the GCC States making efforts; particularly (Oman, Saudi Arabia, UAE,

and Kuwait) to improve their local manufacturing capabilities and the production capacity for

the local population (Al-Essa, 2011). The data supported this hypothesis and therefore it was

accepted.

For the first time this study has examined the centralised regulatory review process in the

Gulf region and identified which steps within the process take the most time. In addition, it

has highlighted the factors which may improve or delay the approval process resulting in

accelerating patients' access to medicines. Furthermore these results may improve the

registration process thereby saving time and resources.

SUMMARY

There was a significant upward trend in the regulatory approval times in the Gulf

Centralised Registration process between 2006 and 2010.

The limited number of meetings per year led to a delay in the feedback for the

submitted files to GCC-DR by the companies.

Further correspondence after registration should be dealt with by individual local

health authorities rather than centrally.

The reference laboratory chosen to carry out the analysis is based on equity of the

number of dossiers distributed between these laboratories, not on the ability of these

laboratories to perform the analysis and that can lead to an increase in the analysis

period.

There was no clock-stop system and this delayed the company response to queries

from the GCC Central registration committee.

The re-registration (renewal) of pharmaceutical companies and their products led to a

reduction in the number of new product applications reviewed by GCC-DR in 2010.

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The lack of a standard assessment template for product evaluation leads to a number

of requests for additional data at different stages of registration. A standard template

could possibly avoid such delays and lead to more consistent outcomes.

Using information technology and e-mails could speed up the registration process

rather than the manual exchange of the product registration files between the

Executive Office and the member states.

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CHAPTER 6

An Evaluation of the Gulf States Views and

Experiences with GCC Centralised Procedure

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INTRODUCTION

The historical implementation of the central registration system was subject to several

criticisms with challenges from both the pharmaceutical industry as well as government. The

GCC-DR received 1,824 medicinal product applications out of which 1,165 (64%)

applications were approved during the eleven years from 1999 to 2010. The pharmaceutical

industry was apprehensive about whether the GCC-DR system would be a hindrance to the

timely approval of medicines in the region while the government officials were concerned

about losing sovereignty to the centralised authority (Hashan, 2005). The collaborative

efforts between the member countries however proved to be effective and substantiated the

support of the GCC-DR system for each GCC country improving the regulatory approval

processes and operation efficiencies at the national level.

Two members from each of the seven GCC countries represent the GCC Central Drug

Registration (GCC-DR) Committee with the current procedure in force and two member

countries are chosen to review a registration dossier. The selection of those countries is

unbiased and purely based on alphabetical order and all the GCC countries are equally

responsible for evaluating the quality, safety and efficacy of medicines. Thus, all seven GCC

countries consisting of Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, UAE and Yemen are

provided with copies of the product registration dossier for their individual assessments. The

member countries meet four to five times a year to discuss the product review reports issued

by the reviewers from each country and an approval decision is made by common agreement.

The only studies that have addressed the GCC region was the one reported by Hashan in

2005 and later by Al-Essa in 2011. They reported that there are three common phases in the

GCC regulatory review process: submission, evaluation, and authorisation. The similarities

and differences in the key milestones and activities in the GCC states made it possible to

propose a new process, which could underpin the degree of standardisation required for a

strong regulatory body that facilitates an effective drug approval process for the region (Al-

Essa,2011). These are the key components essential for the development of a strategic plan

for strengthening drug regulations in the Gulf region. This chapter evaluates the experiences

and opinions of all seven Gulf States regulatory authorities with the GCC Central

Registration Process.

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OBJECTIVES

The main objectives of this study were to:

Evaluate the regulatory views and experiences of all seven Gulf States with respect to the

Centralised Procedure.

Appraise the barriers and opportunities to the full implementation of the Gulf Centralised

Procedure.

Make recommendations to improve the Gulf Centralised system as well as to identify its

future strategy based on the views of the national regulatory authorities.

METHODS

There is a lack of information and research on the GCC Centralised Registration Procedure

and therefore, with this limited information, there is a need to develop suitable measurement

tools in order to obtain the relevant data required for this study. The development of the

assessment instrument was carried out over 5 phases;

Phase 1 – Identify target population and item generation

Phase 2 – Development of themes and item reduction

Phase 3 – Development of the first version of the instrument, Gulf Assessment of

Centralised Procedure (GACP)

Phase 4 – Pilot study

Phase 5 – Development of the final version of the GACP

This final version of the study instrument was sent to the seven Gulf States and followed up

after one month.

RESULTS

This section presents the results from the development of the GACP and the views of the

seven GCC regulatory authorities. For the purpose of clarity the results will presented in two

parts: Part I - The development of the study instrument (GACP); and Part II - The views of

seven Gulf states about the Centralised Procedure.

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Part I: The Development of the Study Instrument (GACP)

Phase 1 – Target population and item generation

An informal interaction and dialogue was held with the members of the GCC-DR which

consist of two individuals (The head of the agency the head of the registration department)

from each of the seven member states in the Gulf region. This allowed the generation of

items for the development of the GACP. In addition, the relevant literature was also reviewed

to inform this phase of the development.

Phase 2 – Development of themes and item reduction

There were a total of five themes emerging from the item generation phase based on

the objectives of the study. The first version of the questionnaire comprised 5 sets of

questions pertaining to the following headings;

Theme 1- Value of centralised procedure consisting of seventeen sub-themes.

Theme 2- Utilization of resources consisting of five sub-themes;

Theme 3- Regulatory expertise consisting of eight sub-themes;

Theme 4- Importance of CP consisting of five sub-themes;

Theme 5- General observations consisting of seven sub-themes.

Phase 3 – Development of the first version of the instrument: Gulf Assessment

of Central Procedure (GACP)

Any item that was mentioned by only one individual was not included in the themes and sub-

themes unless these were country or regulatory authority specific items. Having selected the

themes and sub-themes, these were put in an appropriate structured questionnaire. These

were then reviewed by an expert panel using four appropriate parameters; namely; language

clarity, completeness of the statement, appropriate relevance and scaling. Account was also

taken with regard to the length of the items and their readability.

Phase 4 - Pilot study

The purpose of the pilot study was to assess the practicality, feasibility, applicability and

relevance of the study instrument to assessing the Gulf Centralised Procedure. Having

developed a structured questionnaire it was sent to the head of agency in two GCC States;

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namely Oman and the UAE. Feedback on the first version of the questionnaire was obtained

from Oman and UAE Drug Control Authorities. The pilot study clearly indicated that such a

study into the GCC Central Registration Procedure was essential to bring about

standardisation and harmonisation of procedures. This would inevitably improve the

registration processes for both the applicants as well as the approving authorities.

Based on the feedback from the pilot study, the following item was deleted.

Part 1 – Question 1.1.7: Do you think your agency has the necessary expertise for the

Centralised Procedure and are you willing to contribute?

The following item was added in Part 1 of the questionnaire.

Part 1 – Question 1.1.8: Is your agency willing to contribute to the revision of these

guidelines?

Finally at the end of the questionnaire, six simple questions were added to enable feedback

and opinions about the questionnaire that was used to obtain the information from each of the

Drug Regulatory Authorities in the GCC. This feedback was critical in order to design more

effective assessment instruments for future studies (Figure 6.1).

Phase 5 – Development of the final version of the GACP

Following the pilot study and implementation of the changes suggested by the participating

regulatory authorities, the development of GACP was completed. Thus, the final version of

the instrument consists of 42 items grouped into five major categories. In addition it includes

an introductory page collecting the respondents' personal details (Figure 6.2). The final

version of the questionnaire was sent to all seven Gulf States with a clear guideline on the

aims and objectives of the study and a confidentiality note that would ascertain the

confidential procedure for the collection of data to prevent the identification of individual

respondents. Generally the structure of the questionnaire did not differ from that used in the

pilot study. Only minor adjustments and refinements were carried out to make the final

questionnaire more user friendly and easily understood by the respondents.

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Figure 6.1

123

Figure 6.2

124

125

126

127

128

129

131

The final version of the questionnaire was well received by all the Drug Regulatory

Authorities in the region. They successfully completed the questionnaire and submitted the

completed documents in good time. Their full co-operation was significant for the success of

this study.

Part II: The views of seven Gulf States about the Centralised Procedure

The regulatory authorities who are responsible for the regulation of pharmaceutical products

in the seven Gulf States participated in the survey and a 100% response rating was achieved.

(Table 6.1).

Table 6.1 - List of the seven participating authorities in the Gulf Cooperation Council (GCC)

States

Position Agency Country

Director, Pharmacy & Drug Control Ministry of Health Bahrain

Drug Registration and Release Superintendent Drug and Food Control -

Ministry of Health

Kuwait

Director General of Pharmaceutical Affairs &

Drug Control

Directorate General of

Pharmaceutical Affairs and

Drug Control- Ministry of

Health

Oman

Head of Drug Registration Section Drug Control Department-

Supreme Council of Health

Qatar

Executive Director of Licensing Department -

Drug Sector

Saudi Food and Drug

Authority

Kingdom of Saudi

Arabia (KSA)

Head of Registration and Pricing Department

Drug Control Department -

Ministry of Health

UAE

Member of the board council Supreme board of drugs and

medical appliances

Yemen

Section 1 - Value of the Centralised Procedure (CP)

The complete responses from all GCC member states indicated that the Centralised

Procedure (CP) had indeed contributed to an effective system for authorising medicinal

products for the GCC. This was ascertained from their views that the GCC-DR achieved its

main objective, by providing the best possible scientific opinion for the CP. They also agreed

that the CP has appropriate guidelines for regulatory review in the GCC-DR and that the

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quality of the CP decision-making is satisfactory to good as compared to the national system.

The CP which has been put in place since 1999 is clearly still functioning well as six of the

member countries indicated that the quality of the CP Decision-Making process is good.

Only Saudi Arabia rated the quality of processes as satisfactory.

This signifies that all GCC member countries support the centralised procedure in registering

pharmaceutical products. With the strong support for the CP, four member countries

(Kuwait, Saudi Arabia, UAE and Yemen) indicated that the CP should be extended to other

products to include herbal products, health products and medical devices while Bahrain,

Oman, and Qatar reported that CP procedure should not be extended to other products

(Figure 6.3).

Figure 6.3 The products which could potentially be registered under the Centralised Procedure

The suggested range for the approval timeline for products reviewed in the Centralised

Procedure should be between 6-12 months as indicated by four of the member countries

(Oman, Saudi Arabia, UAE, and Yemen) while Bahrain, Kuwait and Qatar indicated that it

should be 3-6 months (Figure 6.4). The latest data available (2010) indicated that the median

approval time for the Centralised Procedure was nine months (chapter 5).

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Figure 6.4 Proposed approval timeline for products in Centralised procedure

Responses for GCC authorities with regard to improving the CP

Registration process and timelines

The long approval time could be the main obstacle in advocating the CP as the main route for

registration of products in the region. As a result, five of the member countries (Bahrain,

Kuwait, Oman, Saudi Arabia and UAE) agreed that the CP process could be shortened,

although two (Yemen and Qatar) indicated otherwise (Figure 6.5). Bahrain and UAE

indicated that the CP approval time can be reduced by following the exact rules and

regulations in the guidelines by all sectors. In addition, if the verifications were carried out at

the time when the applications were submitted, the time line could be reduced. UAE also

added that another way would be for the reviewing country to send the applications with

preliminary assessment before the committee meets for their discussion as the committee

sees the assessment for the first time at their meeting. To reduce the timeline further, Oman

stated that the member states should not demand more requirements in order to avoid

delaying the whole process; but they should encourage the sponsors to respond expeditiously

to any such requests and by increasing the number of meetings. Kuwait stated that adopting

mutual recognition from mature regulatory authorities would shorten the approval time.

Saudi Arabia, on the other hand, advocated parallel national approvals in the Gulf could also

expedite the process.

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Figure 6.5 – Responses for the GCC authorities with regard to improving the GCC Centralised Procedure

134

Bahrain, Oman, Saudi Arabia and UAE, agreed that certain aspects of the registration

procedure could be simplified to reduce the duration of the CP process. Bahrain stated

that this could be done by developing a written policy for fast track registration, while

Saudi Arabia and UAE advocated the implementation of electronic communication along

with an online submission. Oman stated that the countries must consolidate all the

requests for additional information to be sent to the sponsors as one single batch instead

of in several batches and at different times.

Centralised Procedure guidelines

Bahrain, Kuwait, Oman, Qatar, and Yemen agreed that the CP has appropriate guidelines

for the regulatory review in GCC-DR while UAE and Saudi Arabia report that currently

the guidelines are not adequate. Bahrain, Kuwait, Qatar, Saudi Arabia, and UAE,

indicated that some current guidelines need to be revised or updated. The areas

recommended include GMP inspections, generics registration, contract manufacturing

and biological / biosimilar registration. These guidelines should also be revised on a

regular basis according to international requirements. All the member countries with the

exception of Yemen indicated that they would be willing to contribute to the revisions of

CP guidelines.

GMP Inspections

All member countries indicated their concerns about GMP inspections. Six of the member

countries reported on the quality of expertise for GMP inspectors as well as the quality of

the reports. UAE cited other causes which included the inconsistency of the inspections

and decision-making with regard to classification of defects and time given for corrective

actions and their follow-up.

The effectiveness and efficiency of the GCC-DR

Only Qatar and Oman indicated that the organisation and administration of the GCC-DR

are effective and efficient. Bahrain, Kuwait, Saudi Arabia, UAE, and Yemen reported that

the organisation and administration of the GCC-DR is not effective and efficient. Bahrain,

Saudi Arabia, UAE and Yemen cited the voting system as the contributing factor to the

ineffectiveness which in turn affects the efficiency of the GCC-DR system. Kuwait cited

that choosing the countries to conduct the evaluation affected the effectiveness and

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efficiency. In addition, Kuwait indicated that there is political pressure in some Gulf

States for special consideration to be given to local manufacturers. Bahrain also added

that the SOP for the voting system, which requires total agreement between all member

states, should be written into the policy document.

Contribution to GCC-DR

Four member states (Bahrain, Kuwait, Qatar and Yemen) considered that every agency

made an adequate and appropriate contribution to GCC-DR while the remaining three

member states (Oman, Saudi Arabia and UAE) believe that all agencies did not make an

adequate contribution.

Assessment of Centralised Procedure

In general the GCC Drug Regulatory Authorities are satisfied with the GCC-DR

assessment procedure, implementation of the regulatory guidelines and the availability of

the scientific and technical expertise as is shown in Figure 6.6.

Figure 6.6 – Member states assessment of the Centralised Procedure

However, only two member countries (UAE and Yemen) stated that the quality of the CP

decision-making is better that of their national system (Figure 6.6) while four members

(Bahrain, Kuwait, Oman and Qatar) indicated that it is about the same as their national

system. On the other hand, Saudi Arabia indicated that the quality of the CP decision-making

136

is worse than that of their national system and this is certainly a cause of concern that needs

to be further investigated.

GCC-DR Secretariat activities

The GCC-DR secretariat activities were also evaluated to ascertain the quality and

deficiency, if any, within the organisation. Five member countries (Bahrain, Kuwait, Oman,

Qatar and UAE) indicated that the level of interactions between the GCC-DR Secretariat and

the GCC-DR Committee was good to excellent. Only two member countries (Saudi Arabia

and Yemen) stated that it was only satisfactory. However, all member states, with the

exception of Qatar, indicated that the GCC-DR Secretariat‟s support to the GCC-DR

Committee should be increased (Figure 6.7).

Figure 6.7– Level of interaction between GCC-DR Secretariat and the Committee

The member states added that the Secretariat‟s support could be enhanced by increasing the

number of staff and improving the follow up system between the members. They also

recommended that there should be expert pharmacists at the Secretariat‟s office to validate

the submitted files and this would ensure that the approval process is streamlined. This view

was also reiterated by another member country who stated that the Secretariat needed to

include one or two pharmacists who have enough experience in drug registration and GMP

inspections. Furthermore, since it is an administrative issue, more scientific staff are needed

to organise the dossiers distribution, follow up the status of the companies, and communicate

with other GCC countries members.

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Section 2 – Utilization of Resources

The key issues explored here centred on the allocation of resources to various activities

carried out at the national or centralised level. All member states indicated that limited

resources did pose moderate problems for their agency in relation to their activities with the

Centralised Procedure. However, only Kuwait, Qatar, Saudi Arabia and UAE indicated that

they did not lack the expertise required for the assessment of the Centralised Procedure

applications. Bahrain, Oman and Yemen stated that they did lack the necessary expertise and

that they would be able to overcome this issue by increasing their budget and engaging the

resources required.

Further information was gathered on how the GCC States evaluated their allocation of

resources depending on the various CP activities. Only Oman, Saudi Arabia and UAE

conducted GMP inspections at both national and centralised level (Figure 6.8). Generally

there is an increasing trend for the conduct of GMP inspections at a centralised level.

Figure 6.8 – Number of GMP Inspections conducted by GCC (2008 - 2010)

Based on the data collected from Oman, Qatar and Saudi Arabia (Figure 6.9), it could be

ascertained that the number of product evaluations at a national level is more than those

carried out under the CP. This indicates that most pharmaceutical companies prefer to receive

approval at a national level rather than through the CP. This is further reinforced by the fact

that half of the states indicated that the current CP evaluation system would not be

sustainable due to the lack of resources, together with the current expertise and the heavy

138

national workload. There are a total of 250 internal and external reviewers available in the

GCC. However, this number varied from state to state with Saudi Arabia having the largest

number (121) while Yemen has the lowest number (11). With an increasing number of

products to be evaluated, the number of reviewers within the GCC may not be sufficient to

process the number of new products, thus resulting in the long delay experienced by the

pharmaceutical companies.

From the data collected via the questionnaire (Figure 6.8). UAE conducted a total of seven

GMP inspections at a national level for 2008 and 2009. Oman conducted a total of 29 GMP

inspections at a national level between 2008 and 2010 whereas Saudi Arabia conducted 66

such inspections for 2009 and 2010. It is obvious that there is an increasing trend in the

conduct of GMP inspections at a national level over the three year period (2008 to 2010).

More GMP inspections were carried out centrally in which the total inspections completed by

Kuwait, Oman, Saudi Arabia and UAE for the three year period was 280. There is also an

increasing trend towards central GMP inspections conducted by the four GCC countries from

56 in 2009 to 147 in 2010 which is an increase of more than 100%.

Figure 6.9 – Number of Products evaluated by Oman, Qatar and Saudi Arabia (2008 - 2010)

Product evaluations in Oman, Saudi Arabia, Qatar and at national and central registration

reached a total of 1957 for the period 2008, 2009 and 2010 (Figure 6.9). The highest number

of product evaluations was carried out in the year 2008 with a total of 762 or about 40% of

the total number. Saudi Arabia has the highest total number of products evaluated (841),

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followed by Oman (662) and Qatar (422). This survey also indicated that four member states

did not provide the data for products evaluated by them between 2008 to 2010 for the central

registration. The data for Saudi Arabia was combined with that of the national data as it was

not differentiated when the data was first collected. There is no data available from Bahrain,

Kuwait, UAE and Yemen for centralised product evaluation. In general, it could be

ascertained that the number of products evaluated at a national level is more than those

conducted within the Centralised proceed.

Limitation of resources for product evaluation

All member countries indicated that limited resources posed moderate problems for their

agency in relation to the activities within the Centralised Procedure. However, Kuwait, Qatar,

Saudi Arabia and UAE indicated that they did not lack the expertise required for the

assessment of the Centralised Procedure submissions although Bahrain, Oman and Yemen

indicated that they did lack the necessary expertise. The member states which indicated that

the lack of expertise would be a problem in the future stated that they would seek additional

budget and utilise external reviewers. All member states also indicated that they have a unit

or person within their authority that coordinates CP activities. The entity varies from state to

state depending on the size of the organisation and the related activities.Bahrain, Kuwait,

Oman and Yemen indicated that the current system is not sustainable while the remaining

Qatar, Saudi Arabia and UAE indicated that it is. The countries which indicated that the

current system is not sustainable cited the lack of resources as the main factor. The lack of

expertise is another key concern as well as the national workload as the third factor (Figure

6.10).

Part III: Regulatory Expertise

This section of the report examines the regulatory expertise residing within the national

agencies that would enable the evaluation of different parts of the registration applications.

Table 6.2 provides a summary of all the data pertaining to the internal and external expertise

available in each agency.

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Figure 6.10 – Factors that affect the sustainability of the Centralised Procedure

Generally local internal specialised reviewers are available within each agency and these

account for almost three times the number of external experts. The highest number of internal

experts are involved with the quality data review (30%) while the lowest number is involved

in the review of the biological data (4%) (Table 6.2). Saudi Arabia has the largest number of

internal reviewers totalling 77 while Yemen has the lowest number (11). Oman, UAE and

Yemen rely entirely on internal reviewers. However, there is a direct correlation between the

number of experts, the number of products evaluated and GMP inspections carried out by

these member states (Table 6.3).

Saudi Arabia reported the highest number of evaluators totaling 121 (internal and external)

and they managed to complete 841 product evaluations at national and central levels (2008,

2009 & 2010) as shown in Table 6.3. With their reviewers, Saudi Arabia was able to carry

out 65% of the total GMP inspections carried out at national level. Product evaluations in

Oman, Qatar and Saudi Arabia at national and central registration reached a total of 1,957 for

the period 2008, 2009 and 2010.

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Table 6.2 – Number of internal and external personnel in different areas of expertise within the Gulf States

Gulf States

Quality

data Safety data

Efficacy

data

Pharmacovigil-

ance data

Bioequivalence

data

Biological/

Biosimilar

data

Vaccines data GMP

inspection

Others (if

any) state Total

Int Ext Int Ext Int Ext Int Ext Int Ext Int Ext Int Ext Int Ext Int Ext Int Ext

Bahrain 8 5 0 0 0 0 1 0 6 1 0 0 0 0 9 0 0 0 24 6

Kuwait 8 0 4 0 10 0 0 0 4 0 2 0 0 special

committee

2 0 0 0 30

Oman 9 0 2 0 2 0 2 0 1 0 1 0 2 0 5 0 0 0 24 0

Qatar 3 1 3 1 3 1 1 1 0 0 1 0 1 0 0 0 12 4

Saudi

Arabia

25 2 9 1 9 1 6 13 1 3 2 0 2 0 17 15 6 9 77 44

U.A.E 3 0 2 0 2 0 1 0 2 0 2 0 3 0 1 0 2 0 18 0

Yemen 3 0 0 0 0 0 0 0 1 0 0 0 0 0 7 0 0 0 11 0

Total 59 8 20 2 26 2 11 14 15 4 8 0 8 0 41 15 8 9 196 54

% of

Reviewers 30 15 10 4 13 4 6 26 8 7 4 0 4 0 21 28 4 17 100 100

* Int = Internal

* Ext = External

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Table 6.3 – Relationships between capacity and workload for each Gulf State

(2008, 2009 & 2010)

Gulf States

Internal evaluators

External evaluators

Total Percentage

%

Total Product

Evaluation at National & CP Level

Percentage %

Total GMP Inspections

done at National

Level

Percentage %

Bahrain 24 6 30 12 NA NA NA NA

Kuwait 30 NA 30 12 NA NA NA NA

Oman 24 0 24 10 662 34 29 28

Qatar 12 4 16 6 422 22 NA NA

Saudi

Arabia

77 44 121 48 841 44 66 65

U.A.E 18 0 18 7 NA NA 7 7

Yemen 11 0 11 4 N A NA NA NA

Total 196 54 250 100 1925 100 102 100

NA – Not Available

Section 4 – Importance of GCC-DR

Despite the large number of products being evaluated at a national level, the GCC

member states agreed that the GCC-DR system provides salient advantages to them in

terms of the availability of specialised expertise, training, sharing of

pharmacovigilance data and harmonisation of guidelines. The most valued service is

the collaboration with other national agencies and the provision of guidelines for

harmonisation of the central and national processes. (Figure 6.11).

Figure 6.11 – The value of professional functions to the GCC-DR system by the

Gulf States

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Generally, Bahrain, Qatar and UAE indicated that all the services rendered by the

GCC-DR system are of high value to their respective agencies while Kuwait, Oman

and Yemen indicated that they are of moderate value. Only Saudi Arabia indicated

that the services provided by the GCC-DR system are of little value. The most valued

service is the collaboration with other national agencies and the harmonisation of the

guidelines.

Expertise

In addition, the member states added that by continuously engaging with the GCC-DR

evaluators through discussions and debates, national evaluators would be challenged

to acquire more information and knowledge about the subject of debate and in so

doing expand their experience. These active intellectual exchanges are essential since

those applications which would be evaluated and registered centrally would be then

registered automatically by the individual GCC States.

Training

With regards to training, the respondents stated that such training could be of higher

value if the frequency for shared workshops is increased and becomes an essential

part of each GCC-DR committee meeting attended by reviewers, evaluators and

committee members. Many shared workshops at a GCC level enriched the expertise

of the evaluators who attended. In addition, through such workshops there is a great

potential for the companies to participate at GCC level and opens up the opportunity

to share knowledge and expertise for all participants. To facilitate the training efforts,

it was suggested that training plans be prepared periodically at GCC-DR level.

Collaborations with other agencies

The member states indicated that the exchange of information, experience and plans

should be initiated between all national agencies in the region on a regular basis. This

is clearly beneficial and natural when the committee members are meeting on a

regular basis and have the opportunity to share information. Networking among

member states becomes easier with better established teamwork and this facilitates

communication and enhances further collaborations.

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Sharing of Pharmacovigilance Data

The member states indicated that the sharing of pharmacovigilance data is most

important because at least three member states do not have reviewers in this area.

They added that the potential benefit of the GCC-CP is not fully exploited. If it was,

then the CP will be of very high value to all member countries. It needs more

resources and a specialised unit at the central level equipped with the right software

and supported by unified systems at the country levels. In addition, the respondents

suggested that there should be a system for sharing scientific data between all national

agencies

Guidelines Harmonisation

The member states indicated that the GCC-CP is a great opportunity to harmonise

guidelines and requirements. The GCC States recognised the importance of expediting

these guidelines as eventually the GCC registered products will have the option to be

marketed in their country. If guidelines are not harmonised this would mean

inconsistency in the product quality and the guidelines would also avoid duplication

of effort. All members reiterated that similar registration requirements and

circumstances permit the adoption of guideline harmonisation. In addition, they stated

that the regular updating of guidelines is essential.

Section 5 – General Observations

All the national agencies in the GCC indicated that the integrity of the evaluation

results and better scientific opinion are the key to the success of the centralised

evaluation system (Figure 6.12). Hence, it can be ascertained that the CP has achieved

its mandate to provide a better and efficient registration system in comparison to the

national system. The GCC agencies provided details of the main advantages and

disadvantages of the CP system in comparison to the national system. Their

recommendations to improve the CP system included streamlining and harmonising

the approval process.

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Figure 6.12 – A comparison between the centralised and the national systems

Kuwait, Oman, Qatar, UAE and Yemen indicated that the centralised evaluation

system mostly provided a better scientific opinion than the national system. Bahrain,

on the other hand indicated that the centralised evaluation system always provides a

better scientific opinion than the national system while Saudi Arabia indicated that it

was rarely better (Figure 6.12).

All the GCC States with the exception of Saudi Arabia indicated that the current

centralised system mainly provides consistent evaluations in comparison with national

evaluation. Hence, this is clear evidence that the integrity of the evaluation results and

better scientific opinions are the key to the success of the centralised evaluation

system.

All GCC member countries agreed on having a standard price for specific medicines

throughout the GCC States as shown. However, Qatar was against this, citing the

reason that there would be differences in the proportions of sales and consumption of

medicines between the states and this leads to different profit margins. All GCC

member countries agreed to support the continuity of national registration in parallel

to the centralised procedure while Yemen did not agree to support such a motion due

to limited financial capabilities in comparison to other six member states and for this

reason the Centralised Procedure is a cost-effective option for Yemen.

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Major advantages of the CP system compared to the national system

The major advantages of the centralised procedure as compared with the national

system are shown in table 6.4. Generally, respondents agreed that the first key

advantage of the CP system is the availability of external expertise to complement the

internal reviewers. This enhances the quality of the report and more information is

focused on the registration to ensure that product evaluation is carried our according

to the standards. In this manner, the quality of the product registration is assured

across the GCC States.

Major disadvantages of the CP system compared to the national system

The main disadvantage of the system is the long approval process together with the

differences in recommendations between the national and the centralised procedure.

The inflexibility of the system and the limited number of meetings per year further

delays the whole process thus making the CP system not as attractive as national

registration for companies (Table 6.5).

Practicality and Applicability of the GACP

An evaluation of the GCC states experiences in participating and completing the

questionnaire for this study was carried out. Generally all the participating states

found the questionnaire easy to complete and understand and they found the

questionnaire relevant and clear. Six states found the length of the questionnaire about

right while only Kuwait indicated it was too long. Three states (Oman, Qatar and

Yemen) indicated that they took 30 minutes to complete the questionnaire, Bahrain

took only 20 minutes while Kuwait and UAE took about 120 minutes. Saudi Arabia

could not ascertain the amount of time taken to complete the questionnaires.

Table 6.4 – Summary of the major advantages

1. Better quality scientific evaluation since more than one state is studying the file

2. More scope for exchange of knowledge, ideas and experiences

3. Drug regulatory coordination

4. The burden and workload is divided

5. Better GMP Inspections

6. Guidelines consensus and harmonisation

7. Exchange of Pharmacovigilance reports

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Table 6.5 – Summary of the major disadvantages

1. The delay in registration process in comparison to the national system

2. Conflict of some of the recommendations and/or designs with national system

3. The lack of ability to contact the applicant directly to verify or clarify issues

4. The inability to track the full history of the application as the process of review and

follow up is fragmented

5. Lack of a standardised assessment template

6. The limited number of meetings

7. Increase in the number of applications lead to rushed evaluation by the countries

8. Difficulty in activating some of the recommendations

DISCUSSION

This study was carried out to examine the regulatory views and experiences of all

seven Gulf States with respect to the Central Registration Procedure as well as

identifying the barriers and opportunities to improve the CP. Several challenges face

the GCC health authorities to successfully operate the GCC-DR system. The seven

states identified the need for regulatory reforms during the last 12 years, and this has

enabled the improvement of their national system which has enhanced patients‟ access

to high quality medicines throughout the region. The central registration system has

faced several criticisms both from the pharmaceutical industry who were

apprehensive about whether the GCC-DR system would be an obstacle to the timely

approval of medicines in the region as well as government officials who were

concerned about losing sovereignty to the centralised authority (Hashan, 2005).

However, the effective collaborative efforts between the member states substantiated

the support of the GCC-DR system from each GCC authority with an improvement to

regulatory approval processes and operational efficiencies at the national level.

The most significant finding from this study is that the National Drug Regulatory

Authorities in the GCC believe that the Centralised Procedure (CP) has contributed to

an effective system for authorising medicinal products in the GCC. This is ascertained

from their views that the GCC-DR CP achieved its main objective of providing the

best possible scientific opinion for the CP. They also agreed that the CP has

appropriate guidelines for the regulatory review in the GCC-DR and that the quality

of the CP decision-making is satisfactory to good as compared to the national

systems. Apart from obtaining better quality scientific evaluations, since more than

148

one state is studying the application dossiers, the CP allows more scope for the

exchange of knowledge, ideas and experiences among the National Drug Regulatory

Authorities in the GCC. This results in better drug regulatory coordination within the

GCC. As a result of this study it could be ascertained that product evaluation at a

national level is more frequently carried out than at the CP as most pharmaceutical

companies prefer to have their products reviewed at a national level. As an outcome

of this more than three of the states indicated that the current CP evaluation system

would not be sustainable due to the lack of resources and the heavy national

workload.

This lack of resources presents moderate problems for the GCC States in relation to

their activities within the Centralised Procedure. The GCC States recognise the

importance of resources, both human and financial, for the development of strong

regulatory systems. However, the lack of resources can be compensated to some

extent by effective collaboration among countries and information sharing (WHO,

2008). Furthermore, the GCC authorities are able to allocate financial resources due to

their strong economic status, but the availability of human resources and expertise

remains a challenge for the development of a robust drug regulatory system.

There are a total of 250 internal and external professional evaluators available in the

GCC. However, this number of evaluators varied from country to country with Saudi

Arabia having the largest number (121) and Yemen having the lowest with only 11.

With the increasing number of products to be evaluated, the number of specialised

experts within the GCC may not be sufficient to process product registration, which

will result in further delays for pharmaceutical companies. Increasing the number of

external experts in the GCC States may be the best solution for this problem to reduce

the workload on the internal reviewers but this may have a possible impact on the

quality of the review.

Pharmaceutical companies have mixed feelings about whether they can gain faster

marketing authorisation through the national regulatory systems or the regional

centralised system. The goal of any pharmaceutical company is to complete the

registration requirements and gain access to the national GCC markets in the shortest

possible time. In the end, two approval routes, national and centralised exist side-by-

side in the GCC region. For the centralised system to dominate, member states should

seek ways to increase their collaborative efforts to bring their systems closer towards

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standardisation that would facilitate the regional registration process and maintain

patients‟ access to safe and effective medicines within a reasonable time frame. The

long approval timeline in the CP approval process is a major obstacle to advocating a

central approval procedure. The majority of GCC States agreed that the CP process

should be shortened and they indicated that the timeline for the Centralised Procedure

could be reduced by:

All member states following the GCC guidelines.

The verifications of the registration documents being carried out at the time of

submission.

The reviewing agency sending the applications with preliminary

remarks/deficiencies before the committee meets for their discussions.

The member states not demanding additional data to avoid delaying the whole

process.

Increasing the number of GCC-DR meetings.

Taking in to account the prior approval by mature regulatory authorities.

One way forward is to consider the verification model for the assessment of a new

registration dossier. This model can be used for applications for products that are

registered in a reference country with established mature regulatory authorities

(McAuslane et al., 2009). If not, a more specialised review can be considered for

products which are not registered elsewhere. Singapore, for example, conducts a

verification review for all types of medicines which are previously authorized by at

least two reference authorities, except for biological and biotechnology products.

The member States also agreed that certain aspects of the registration procedure could

be simplified to reduce the duration of the CP process, these aspects are to:

Implement electronic communication together with online submissions.

Send all the requests for further information or clarification questions to the

companies at one time instead of in several batches.

Have a written policy for fast track registration such as life-saving anti-cancer

and anti-HIV drugs.

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Despite the large number of products being evaluated at a national level, the GCC

member states agreed that the GCC-DR system provides significant advantages in

terms of the availability of specialised expertise, training, sharing of

pharmacovigilance data and harmonisation of guidelines. The most valued service is

the collaboration with other national agencies and the provision of guidelines for

harmonisation of the central and national processes.

The GCC agencies agreed that the key advantage of the CP system is the exchange of

knowledge and information between the member States. This enhances the quality of

the report and more attention is focused on the registration to ensure that the product

evaluation is carried out according to set standards and thus the quality of the product

registration is assured across the GCC States. In addition, the inflexibility of the

system and the limited number of meetings per year further delays the whole process

thus making the CP system less attractive for companies to obtain their product

approval.

SUMMARY

This study has demonstrated that the GCC-DR Centralised Procedure achieved

its main objective by providing the best possible scientific opinion. Appropriate

guidelines for the regulatory review in GCC-DR was of considerable value while

the quality of the CP decision-making ranged from satisfactory to good as

compared to the national system.

All member countries indicated that limited resources did present moderate

problems for their agency in relation to their activities with the Centralised

Procedure.

There are more products being registered at a national level than at the CP.

Despite the preference to evaluate products at a national level, these agencies

agreed that the Centralised Procedure (CP) had indeed contributed to an effective

system of authorising medicinal products for the GCC by providing the best

possible scientific opinion for the quality of the CP decision-making as compared

to the national system.

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The main disadvantage of the system is the long process to obtain the approval.

The inflexibility of the system and the limited number of meetings per year

further delays the whole process thus, making the CP system less attractive for

companies.

The member countries recommended that the GCC-DR streamlines and

harmonises the CP approval process with national systems in order to improve

the effectiveness and efficiency of the Centralised Procedure.

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CHAPTER 7

An Evaluation of the Pharmaceutical

Companies Experiences with the GCC

Centralised Procedure

153

INTRODUCTION

The primary aim of drug regulation is the protection of public health. Hill (2004)

suggested that for some the balance between controlling pharmaceuticals in the

interests of ensuring public health and encouraging the development of

pharmaceutical products has shifted in favour of the innovative industry. However,

others perceive regulation as an obstacle to the availability of medicines in national or

regional markets and this has placed a significant demand on regulators to expedite

reviews and evaluations to approve medicines (Hill, 2004). Nevertheless, medicines

regulation is the foundation of any country‟s national drug policy that ensures a viable

pharmaceutical industry as well as a high standard drug approval process.

The establishment of the International Conference on Harmonization (ICH) between

the United States, Europe and Japan in 1990 reflected a need felt by the research

based industry and certain governments to streamline the approval process for the

registration of new medicines (Mallia-Milanes, 2010). The term harmonisation refers

to the standardisation of technical requirements for medicines regulation, of which the

requirements relate to quality, safety and efficacy of medicines and this can differ

from one country to the other. Since its inception, ICH has evolved, through its

Global Cooperation Group (GCG) to respond to the increasingly global phase of drug

development. The GCG was originally formed as a subcommittee in 1999, in response

to the growing interest in ICH guidelines beyond the ICH regions and one such

harmonisation was that of GCC, the Gulf cooperation council. This collaborative

mechanism ensures ensure a more transparent and streamlined process for the

marketing authorization of pharmaceutical products in the GCC region.

The Gulf centralised registration process is facing several challenges which lead to

delays in patients‟ access to medicines with the need to re-register products in

individual countries after central registration. In addition there is a requirement to

register the manufacturer prior to submitting the product file to the Central

Registration Office. Currently there is the need to establish effective methods for

sharing the workload amongst the regulatory authorities in the GCC states. A paucity

of studies at the GCC level, probing into the views and experiences of individual

pharmaceutical companies with the GCC central registration system, has made its

improvement a constant challenge. Hence, this study is envisaged to explore the

importance of the system and identify challenges and critical success factors to

154

enhance the effectiveness and efficiency of the central registration procedure.

Patients benefit from the timely access to safe and effective therapies while

pharmaceutical companies are able to market the product sooner and generate

revenues for further research and development.

OBJECTIVES

The objectives of this research were to:

Evaluate the experiences and views of pharmaceutical companies with respect to

the central registration review process.

Appraise the barriers and opportunities to the implementation of the Gulf

Centralised Procedure.

Make recommendations to improve the Gulf Centralised system as well as to

identify its future strategy based on the views of the pharmaceutical companies.

METHODS

With limited information and the lack of data on the GCC Central Registration

Procedure, there is a need to develop suitable measurement tools in order to obtain the

relevant information required in this study. In Chapter 6, an assessment tool for the

evaluation of the Centralised Procedure by the Drug Authorities in the GCC was

developed and the findings reported. In this Chapter, the emphasis will be on the

pharmaceutical companies and evaluating their experiences in obtaining approval for

their products. The development of the assessment instrument was completed over 5

phases;

Phase 1 – Identify target population and item generation

Phase 2 – Development of themes and item reduction

Phase 3 – Development of the first version of the instrument, Companies Assessment

of Centralised Procedure (CACP)

Phase 4 – Pilot study

Phase 5 – Development of the final version of the CACP

This final version of the study instrument was sent to 100 pharmaceutical companies

(50 generic and 50 innovative) and followed up after one month.

155

RESULTS

This section presents the results from the development of the CACP and the views of

pharmaceutical companies. For the purpose of clarity the results will be presented in

two parts: Part I - The development of the study instrument (CACP); and Part II - The

views of the pharmaceutical companies about the Centralised Procedure

Part I: The Development of the Study Instrument (CACP)

Phase 1 – Target population and item generation

An informal interaction and dialogue was held with a number of pharmaceutical

companies at a consultation meeting organised by the GCC-DR in the spring of 2010.

This allowed the generation of items for the development of the CACP. In addition

these items were cross-referenced with the Gulf States instrument in order to ensure

that relevant items were also retained for the CACP.

Phase 2 – Development of themes and item reduction

There were total of five themes emerging from the item generation phase based on the

objectives of the study. The first version of the questionnaire comprised five sets of

questions pertaining to the following headings;

Theme 1- General Introduction consisting of eight sub-themes;

Theme 2- Centralised Registration Procedure consisting of eight sub-themes;

Theme 3- Interaction with GCC-DR consisting of six sub-themes;

Theme 4- Scientific Opinion consisting of nine sub-themes;

Theme 5- General observations consisting of eight sub-themes.

The General Information included their preference for using the system, national vs.

centralised, data on the number of products submitted and registered through the

centralised procedure, along with their experience and opinion of the system itself.

Theme 2 deals with the guidelines, quality of scientific opinions, appeal procedure,

implementation of the common technical document submission format and

harmonisation of the procedure. Interaction of the company with GCC–DR with

respect to the quality and timing of information received, their relationship with

individual member countries, influence of the pharmaceutical companies on the

156

GCC–DR formed Theme 3 Scientific opinion in terms of regulatory expertise was

included in Theme 4, and Theme 5 contains general observations from pricing to

recommendations to improve the procedure, their views on the present system and

future strategies.

Phase 3 – Development of the first version of the instrument, Companies

Assessment of Central Procedure (CACP)

The selected themes and sub-themes were put into an appropriate structured

questionnaire. These were then reviewed by a social science expert using four

appropriate parameters; namely; language clarity, completeness of the statement,

appropriate relevance and scaling. Account was also taken with regard to the length of

the items and their readability.

Phase 4 – Pilot study

The purpose of the pilot study was to assess the practicality, feasibility, applicability

and relevance of the study instrument to assessing the Gulf Centralised Procedure

from the companies‟ perspective. The structured questionnaire was sent to five

targeted companies (two innovative and three generic).

Feedback from the first questionnaire was obtained from these companies. This pilot

study clearly indicated that such a project into GCC Central Registration Procedure

from the pharmaceutical companies‟ perspective was essential to bring about

standardisation and harmonisation of the approval process. This would inevitably

improve the registration system for both the applicants as well as the approving

authorities. Based on the respondents feedback minor changes were made to the

questionnaire. These changes included adding refinement to questions 2.1 and 2.2 in

Part 2 and repositioning questions 3.3 and 3.4 in Part 3 of the questionnaire. Finally,

six simple questions were added to the questionnaire to obtain the views of the

respondents about the practicability, applicability and relevance of the CACP. This

feedback was critical in order to design a more effective assessment instrument for

future studies (Figure 7.1).

157

Figure 7.1

158

Phase 5 – Development of the final version of the CACP

Following the pilot study and implementation of the changes suggested by the

participating companies the development of CACP was completed. Thus, the final

version of the instrument consists of 39 items grouped into five major categories. In

addition it includes an introductory page collecting the respondents' personal details

(Figure 7.2). The final version of the questionnaire was sent to 100 companies who

had registered their products through the either centralised registration procedure

and/or national registration systems. The questionnaire was sent with a clear guideline

regarding the aims and objectives of the study with a statement assuring them of the

confidentiality of the study.

Part II: The views of the pharmaceutical companies about the

Centralised Procedure

An analysis of the target audience was carried out by listing all pharmaceutical

companies who had interactions with the national registration system and/or the CP in

the GCC region. This list of the companies registered with the CP was obtained from

the GCC-DR office in Saudi Arabia. The profile of each company was analysed to

ascertain their suitability and their willingness to provide information for the study.

Fifty generic and 50 innovative companies were selected for the study from the list of

registered companies, half of them with experience registering their products through

the CP while the other half had the experience of registering their products through

the national system.

Characteristics of the study participants:

The CACP was distributed to 100 pharmaceutical companies out of which 30

responses were received (30%) (Appendix 1). The remaining, who did not respond,

could be categorised into four groups:

1- Unwilling to participate

2- Lack of experience

3- Lack of response, and

4- Sensitivity of the information required

159

Figure 7.2

161

161

162

163

164

165

The CACP scores:

In order to answer the main evaluation questions covering the experience of these

companies with GCC-DR Central Registration Procedure the results are presented

under five sections.

Section 1 – Companies general views about the Centralised procedure

In this section, the companies‟ experiences in registering their products through the

Centralised Procedure were examined. Their preference for using this system, national

versus centralised was determined. Data on the number of products submitted and

registered through the centralised procedure, along with their experience and opinion

of the system itself were also recorded. Generally, more than half of the companies

who responded preferred the national registration procedure to the Centralised

Procedure (Figure 7.3) The majority of the pharmaceutical companies preferred to

register their products through the national system than the centralised system. Eleven

innovative companies preferred the national system rather than the CP while six

generic companies choose the national system instead of the CP. Nineteen companies

had submitted their products for registration under the centralised system, while more

generic companies (12) had submitted their products to the CP than the innovative

companies (Figure 7.3).

Figure 7.3 – Number of companies and their preferred pharmaceutical registration

system

166

Only the 19 companies who had the experience of registering their products through

the CP were able to provide critical information on the strengths and weaknesses of

the CP registration system. The main reasons for choosing the centralised registration

system over the national system are illustrated in Figure 7.4. This shows that 14

pharmaceutical companies were able to meet the requirements to GCC tender

specification, convenience (12 companies) and timeliness of registration,

cost/resources required and ease of subsequent CP registration. One of the

respondents indicated that the central registration team is more accessible, easier to

communicate with, flexible and understanding about the companies‟ issues. It is also

faster in approval than the national authority. Another respondent indicated their

choice of product registration system would be dependent on their company‟s strategy

and the nature of the product.

Figure 7.4 – Reasons for companies preference in using the Centralised

Procedure for product registration

*Other Factors

1. Central registration team more accessible, easier to communicate with flexible and

understanding about the companies’ issues. Faster in approval than the national and is a

respectable authority.

2. Depending on the company strategy and the nature of the product

Figure 7.5 shows the reasons why pharmaceutical companies did not prefer the

centralised system. Eight of the companies stated that their product strategy was

aligned to the registration in selected GCC states, hence the preference for national

registration. The timeline for registration and the experience with the national systems

registrations resulted in a total of seven responses. The rest cited the cost and resource

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requirement and subsequent pricing of products as well as a concern over possible

rejection by GCC-DR. One of the companies highlighted that for highly specialised,

orphan, and important products, they preferred to go via the national procedures, since

they found it more transparent and easier to communicate with the regulatory

authorities. The CP is a strategic option, but due to a limited number of GCC-DR

annual meetings, the companies cannot take the risk for important products that are

required to be available in the countries faster, since CP may take a longer time

compared with national registration.

Figure 7.5 – Reasons why companies did not prefer the Centralised Procedure

*Other Factor

Due to the limited number of GCC-DR annual committee meetings, the company cannot take the risk

for important products registration that must be made available in the countries quickly, since it may

take a long time to receive GCC-DR comments.

The number of products submitted for approval to the Centralised Procedure by 13

companies varied between 29 to 75 submissions annually (Figure 7.6). The year 2010

saw a substantial increase in the number of applications by almost 3 times as

compared to the previous year (2009). This could be an indication that the companies

realised the benefits of obtaining an approval from the GCC-DR to market their

products to the seven member states seamlessly. The total number of products

submitted from 2006 to 2010 was 212 while the total products registered were 210 for

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the four years (2006 to 2009). An upward trend can be seen in product submissions

and product registrations under the CP system. This clearly indicates that though there

were challenges in processing the products for approval at GCC-DR level, it certainly

is gaining recognition as a viable option. Twenty companies believed the quality of

decision-making of the Centralised Procedure to be good or excellent while seven

companies stated that it was only satisfactory.

This is an indication that although there are issues with the centralised registration

system, the quality of its decision-making is still satisfactory for most companies

(Figure 7.7). Although some companies had no experience of registering their

products through the CP they were still able to provide their opinion about this

system.

Figure 7.6 – Number of products submitted and approved through the Centralised

Procedure

Twenty companies stated that it took them more time to register their products

through the centralised system. The pharmaceutical companies also stated that the

limited number of meetings by the Central Committee was one of the main causes of

the delay in product registration; thus their preference for national registration. The

delay in product registration is also attributed to the fact that the submission of the

documents for review and approval by the Committee has to be done earlier before

the summer hiatus if the companies wish to complete the procedure in good time.

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Figure 7.7 –The quality of decision-making of the Centralised Procedure

However, unlike the national registration procedure in which both the product and the

pricing registration could be done concurrently, the company has then to wait for the

product approval centrally before proceeding with the pricing approval locally.

Further delays in product approval and registration in the CP were caused by long

technical documents evaluation, distribution of the files for the reference countries for

evaluation and analysis feedback and a long queue for submission and review by the

committee. The issue of sequentially processing for national registration after the

Centralised Procedure added a further delay to the approval process and it could take

between 1.5 to 2.5 years for approval to be attained for each product. Furthermore,

with so many issues to be discussed in the CP Committee meetings coupled with the

limited number of meetings per year meant approval and registration issues would

take a longer time to be resolved, hence lengthening the approval process. More

delays are caused when evaluators waited until after the CP meetings to pass their

comments and requests for additional information instead of asking for this

immediately on reviewing at the first stage.

Twenty-seven companies indicated that the timelines for registration in the

Centralised Procedure could be shortened and twenty of these companies also stated

that by having more GCC-DR meetings this could be achieved. Others believed that

having additional technical expertise and conducting parallel processing of the

laboratory tests and the CP registration could also shorten the process however,

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Parallel processing was induced in 2011. Figure 7.8 summarises how certain aspects

of the registration procedure could be simplified. Twenty of the companies also

indicated that certain aspects of the registration procedure could be simplified. The

majority of these respondents believed that electronic submissions and automation of

some of the processes could assist in simplifying the Centralised Procedure as a whole

and hence shorten the whole process. Others indicated that the technical evaluation

could be simplified by relying on documents submitted to GCC since these were the

same documents already submitted and approved in the US/UK and other reference

countries. Finally, 16 of the companies indicated that the current registration fee for

the Centralised Procedure is reasonable while 11 of the companies stated that it is too

high. Hence, the cost factor from the registration perspective is not the key reason

why companies preferred the national registration system to the Centralised Procedure

to obtain approval for their products.

Figure 7.8– Companies’ suggestions on how certain aspects of the registration procedure

could be simplified

*Others

1. The pricing procedure in the individual GCC states should be in parallel with the CP

Registration.

2. The communication with the companies could be via email or other means of electronic

transmission.

3. Stop the site inspection if the site was in a reference country and has the appropriate GMP

and manufacturing license (same as the national registration).

4. Have one registration certificate for all GCC states from GCC-DR (once registered, no need

to submit again per each country to gain approval).

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Section 2 - Centralised Registration Procedure

The companies experiences in submitting and registering products under the CP is

reviewed in this section. Generally the companies were satisfied with the quality of

the guidelines and scientific advice as well as their opinions on the implementation of

the Common Technical documents, pharmacovigilance procedures, and transparency

of the Centralised Procedure. In addition, the majority of the companies also agreed

that the CP led to the harmonisation of national procedures in the GCC legislation.

Half of the companies indicated that the Centralised Procedure guidelines were easy

to understand (eight generic and seven innovative companies), 10 companies (six

innovative and four generic companies) stated that the guidelines were not always

clear and another three companies indicated that they were generally unclear (Figure

7.9). Those who stated that the guidelines were not always clear further provided their

explanation for their choice. They pointed out that there were no guidelines for all

registration requirements (e.g. available guidelines are for Stability Studies and

Bioequivalence study only). Variations to the guidelines were also not available. The

biotechnology products registration guidelines were very short and ambiguous and

many of the requirements, that the committee asked for, were not included. In

addition, they commented that the committee sometimes went outside the guidelines

and asked for additional requirements found in other international guidelines

(oscillating between EU and FDA, especially with stability and Bioequivalence).

They also stated that the patient information leaflets (PIL) requirements were not clear

and many times the committee asked for amendments for the PIL that was

internationally recognized. Hence, they were not provided with clear criteria in this

matter. Finally, they added that the registration certificates for manufacturing sites

were not harmonized with regards to the nomenclature of the production lines which

created confusion when required to register a product from such a site later.

Quality of GCC-DR Scientific Opinions

The majority of the companies indicated that the quality of the GCC-DR scientific

opinions ranged between good to excellent while five companies stated that it was only

satisfactory (Figure 7.10). It can be concluded that the pharmaceutical companies in

general were satisfied with the quality of the GCC-DR scientific opinions despite the

hassle and the issues faced in getting their products registered through the Centralised

Procedure.

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Figure 7.9 – Companies’ view on the Centralised Procedure guidelines

Figure 7.10 – Companies’ views on the quality of the GCC-DR scientific advice,

efficiency and effectiveness of the centralised pharmacovigilance procedures and the

transparency of the Centralised Procedure

Similarly, the majority of the companies also stated that the current appeal procedure

was sufficient in the case of a negative opinion issued by the GCC-DR, although, 10

companies felt otherwise. They further added that there should be meetings between

the GCC-DR and the companies so that these companies could explain the reasons for

the appeal which may not have been understood by the committee previously.

Therefore, these views should be considered by the member states. Also, the GCC

needs to take in to account the registration certificates issued from the mature

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regulatory authorities such as FDA and EMA. Other respondents also stated that the

GCC-DR had no experience in dealing with appeal cases and hence there was neither

any clear timelines nor clear answers provided to the companies as justification for the

rejection. This made it very difficult for the companies to convince all the members of

the committee of their positive opinion or challenge the rejection decision. There were

also no response received by the companies in case of a negative opinion by the GCC

and the submission of their appeal document.

Seven companies indicated that the implementation of the common technical

document format would be a barrier to their company‟s submission of product

registrations through the Centralised Procedure. Nevertheless, they also stated that to

work in the same CTD format for all the GCC countries individually in addition to

GCC-CP, would encourage many manufacturing companies in the region to obtain the

approvals from GCC-CP. However, the resources, specialised personnel and hands-on

training are not enough. At present, not all the member states are at the same level for

receiving and processing CTD applications. Most medium size and Arab companies

did not have any idea about such a format and they would need a considerable time

before they could fulfil these requirements. This would be very difficult for these

companies and would be costly to submit the same documentation but in a “different”

ICH format. Moreover, such a requirement has been applied without prior notice or

time allowance. As a result, it may take a much longer time to get the final approval.

Some form of flexibility should be accepted as there are old and rare products which

do not have a CTD dossier. This new requirement would also mean that there would

be additions in the required documents. Some of these documents and tests may

require more time to be prepared, thus, this would delay the process of registration.

The efficiency and effectiveness of the GCC centralised pharmacovigilance

procedures

The majority of the companies who responded were satisfied with the efficiency and

effectiveness of the GCC centralised pharmacovigilance procedures as the GCC-DR

had continued to be vigilant and monitor Adverse Drug Reactions (ADR) of

medicines speedily. In addition, currently the companies believe that the current GCC

guidelines for pharmacovigilance are not clear, even though the Saudi FDA guidelines

are well recognised. However five companies (Figure 7.10) indicated that although

the efficiency and effectiveness of the GCC centralised pharmacovigilance procedures

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were poor, they were not aware of any pharmacovigilance systems in the region being

implemented. However, the five companies had strict internal systems related to

safety, PV and Risk Management Plans (RMP).

The transparency of Centralised Procedure

Five companies indicated that the transparency of the Centralised Procedure was

excellent because the GCC-DR was open in their communications; it was easy to meet

the central organization team member who was willing to simplify the issues and had

great understanding with a high level of transparency. On the other hand half of the

companies stated that although the CP transparency was good as there were clear

guidelines, refinement was needed in the follow-up of the application process.

Overall, 70% of the companies disagreed that the Centralised Procedure should be

made compulsory for certain range of products. However, six companies agreed that

the Centralised Procedure should be made compulsory for the following range of

products:

Prescription only Medicine

Narcotics and controlled drugs

Medicinal, Herbal and Heath products

Biotechnology products especially coming from non stringent countries.

Vaccines

Life saving medicines and products that are crucially required in these markets

Finally, 18 companies agreed that the Centralised Procedure has contributed to the

harmonisation of the legislation throughout the GCC while eight of the respondents

did not agree.

Section 3 - Interaction with Gulf Central Committee for Drug Registration

(GCC-DR)

Generally, the companies were satisfied with the level of interaction with the GCC-

DR in terms of the quality of the information received and the relationship between

the authorities. The majority of them also agreed that the pharmaceutical industry can

influence the GCC-DR Centralised Procedure through sharing of knowledge and

experiences and promoting closer collaboration.

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Based on the same data, more than 15 companies were satisfied with the timing of the

registration procedure at GCC-DR while six companies indicated that the timing of

the registration was poor. Nineteen companies indicated that their relationship with

the Registration Department of the GCC-DR was good or excellent and 22 companies

indicated that they were satisfied with the relationship (Figure 7.11).

Figure 7.11 – Companies’ view of the level of interaction on the quality of information

received, timing of the registration procedure and their relationship with the

Registration Department of the GCC-DR

Although many companies refrained from commenting on their relationship with the

GCC-DR because of its sensitivity, however they indicated that the relationship could

be improved. Some of the ways in which this could be improved are summarised in

Figure 7.12. Three companies suggested that the increased sharing of knowledge

through training, seminars and workshops would promote more interactions between

the companies and the GCC-DR especially in discussing changes to regulations and

procedures. This would significantly improve the relationship between companies and

the GCC-DR and could contribute to providing healthcare benefits to GCC states.

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Figure 7.12 – Companies’ views on some of the ways to improve the relationship

between the companies and the GCC-DR

Ten companies suggested that there should be an increased number of meetings as

well as improved communication between the GCC-DR and the pharmaceutical

companies. Through openness and regular communication with the companies and

having open dialogue and meetings to determine companies needs, the relationship

between the two organizations would be improved. This would also promote

consistency in decision-making and provide transparency and clear justifications

should there be any rejections in the future.

One of the companies indicated that the number of GCC-DR staff is low as compared

to the considerable amount of work they have to carry out; therefore the quality of the

relationship is adversely affected. Hence, increasing the number of GCC-DR staff is

essential to ease the workload and improve their relationship with the companies.

Others suggested that the GCC-DR must work as the centre for all GCC

Pharmaceutical companies. They should promote regular activities such as running

conferences and training courses in different fields of pharmaceutical manufacturing,

case-studies, training on registration guidelines in GCC and in other regulated

markets. Also, it should include distributing statistics on GCC pharmaceutical

companies and medicines, improving knowledge on pharmaceutical technology

among pharmaceutical companies and linking with other international conferences on

medicines and related issues. In addition, they suggested that by providing electronic

online services, the companies would be able to track the progress of their product‟s

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registration status and comments, anytime, anywhere. This would greatly facilitate

communication with the GCC-DR and expedite information requests. Twenty

companies agreed that the pharmaceutical industry can influence the GCC-DR

procedure and that it could be done in the following manner;

Through sharing of knowledge, experiences and interaction, the

pharmaceutical companies could provide support at any level through their

worldwide experience with authorities and regulators. As an important partner

in the registration process, the companies would be able to provide the GCC-

DR with effective and efficient services and quality products.

The pharmaceutical companies could contribute to drafting and refining the

guidelines and GMP inspection systems to make them more effective and

efficient.

They could assist the GCC-DR in streamlining the procedure in order to

improve and expedite the registration process.

They also added that private accredited laboratories could be engaged to help

facilitate the procedure and by giving priority to the registration of new

products from local industries.

Section 4 - Scientific Opinion

Twenty companies indicated that the scientific opinions from the CP were relevant

with respect to their regulatory expertise. Generally, they were satisfied with the

quality and safety data, bioequivalence studies and vaccines data provided by the

GCC-DR experts for the pharmaceutical products registration and approval process.

Generally, half of the companies indicated that the quality of the assessment provided

by CP experts for safety, efficacy, pharmacovigilance, bioequivalence studies,

biological/biosimilar, vaccines data and GMP inspections were good or excellent

(Table 7.1) with only six companies indicating that the assessment for efficacy data,

pharmacovigilance data, biological/biosimilar and GMP inspections were poor. There

was also a high percentage of companies (36%) who did not provide their responses

for this question which probably indicated that they may not have had the appropriate

experience in these areas.

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Table 7.1 – Companies’ opinion regarding regulatory expertise within the GCC-DR

Review Expertise Excellent Good Satisfactory Poor Total

Quality data 5 16 3 0 24

Safety data 5 13 5 0 23

Efficacy data 5 14 3 1 23

Pharmacovigilance data 2 6 8 3 19

Bioequivalence studies 6 7 6 0 19

Biological/biosimilar 2 8 1 1 12

Vaccines data 3 7 1 0 11

GMP inspections 9 10 1 1 21

Section 5 - General observations

The majority of the companies believe that the CP has a more efficient registration

system as compared to the national system and indicated the main advantages and

disadvantages of the CP system based on their experiences. Three companies

indicated that the current centralised evaluation system always provides a better

scientific opinion/outcome than the national system, while five companies stated that

this occurs frequently. Nine companies indicated that the GCC-DR sometimes

provided better scientific opinion/outcome than the national system while three

companies stated that this happened rarely. However, more than half of the companies

agreed that the current centralised evaluation system did provide better scientific

opinion/outcome than the national system (Figure 7.13).

Nine companies agreed that the current centralised system provided consistent

evaluations in comparison with the national evaluation while ten companies indicated

that this happened sometimes and only six companies stated that this happened rarely

(Figure 7.13). Clearly, attaining a standard consistency of the evaluation reports

continuously is critical to the quality and efficacy of the centralised GCC-DR

procedure. Half of the companies did not agree with the idea of having a standard

price for specific medicines throughout the GCC states and the reasons for their

disagreement are shown (Figure 7.14). The most critical aspect, as cited by 14

companies, is the difference in economic aspects of the various GCC states as

differences in the cost of living and demographics would impact the volume of the

products, hence the price of the medicines.

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Figure 7.13 – A comparison of the companies’ views of the national versus the

centralised system with respect to scientific opinion and consistency of evaluations

Figure 7.14 – Companies’ views as to why a standardised pricing is not appropriate

It is therefore a complex task to set a standard price for specific medicines throughout

the GCC states. Finally, 80% of the companies stated that they would support the

continuity of a national registration in parallel to the Centralised Procedure while 20%

of the companies would not.

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Advantages of the Centralised Procedure compared to the National System

Fourteen companies who responded to the survey clearly indicated that one decision

from the GCC-DR has a considerable advantage as the product could be promoted

faster, easier and is highly recognisable in the seven GCC states. The advantages of

the Centralised Procedure as compared to the national system are as follows;

a. Harmonisation of procedures

One approval procedure, one set of documents for the entire approval process

and one file with the same format for one submission. The procedure is much

simpler and less complicated. This would save time and effort and promote

transparency.

b. One decision for all seven countries

In this way medicinal products can be available to all GCC States at the same

time once they have been approved by GCC-DR. This facilitates the

registration of manufacturing sites in one step. Hence, it would reduce the

burden on internal company resources to prepare “dossiers” for additional

registration.

c. Others

Collective and diversified opinions from the different GCC states add

more value to the CP decision.

Products registered at the GCC level will add value to the company

and it will open new markets for its products,

The implementation of CTD format in the central and national levels.

Proceed with other countries with less documentation.

If there are no major objections from the committee, then the approval

is faster

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Disadvantages of the Centralised Procedure compared to the National

System

The major disadvantage of the CP as compared to the national system is that it is a time

consuming and costly process, followed by the inconsistency of the process and the

insufficient number of meetings. The companies also stated that the need to re-submit

product files at a national level after approval at the Centralised Procedure is another

disadvantage. Sometimes more details are required in terms of the assessment of products

by the national system compared to the Centralised Procedure. The companies are also

concerned about the possible rejection by GCC-DR that would affect other GCC

countries national registration. They stated that although the products are acknowledged

by national authorities as final approval in one or more of the member states, they still

need to go through the full CP process. By not using communication such as electronic

mail, the GCC-DR further delays any correspondence with the companies which could

facilitate the registration processes. In addition, the companies also indicated that inter-

committee politics may affect certain decision-making outcomes which are not

standardised.

The three major disadvantages of the Centralised Procedure as compared to the national

system are as follows;

Time consuming procedure and costly process - The procedure of registration

involves a very lengthy period both at the quality control laboratory for analysis as

well as at the committee level. Feedback is not clear and there is no direct

communication with principal companies. Coupled with the high registration fee, the

long registration process is the key disadvantage of the Centralised Procedure.

Inconsistency of the process – The absence of guidelines leads to inconsistency in

the opinions and some radical differences occur at national level. Many of the

documents submitted to the GCC are requested again at a national level after GCC

approval. Some states do not accept registration without prior GCC-DR approval.

National authorities do not approve the product for distribution even after attaining

GCC-DR registration through the CP system.

Quarterly meetings - Once a quarter committee meetings is not sufficient to

process the application. Hence, the long delay in the approval process.

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Practicality and Applicability of the CACP

An evaluation of the companies‟ experiences in participating and completing the

questionnaire for this study was carried out. Twenty-two companies (88%) found the

questionnaire easy to complete while 12% of the companies found it difficult (Figure

7.15). Twenty-four (96%) of the respondents found the questionnaire easy to

understand while only one company found it difficult to understand. Nineteen (76%)

of the respondents found the questionnaire relevant while only 3 companies (12%)

found the questionnaire not relevant. One of the companies stated that the

questionnaire was not always relevant. Twenty-three (95%) of the respondents found

the questionnaire clear while only one company stated that the questionnaire was not

clear. Twenty-one 83% of the companies participating in this study found the length

of the questionnaires about right. Only 17% of the companies indicated that the

questionnaire was too long. Nine (30 %) of the companies took about 30 minutes to

complete the questionnaire while 35% took more than 30 minutes and the remaining

35% took less than 30 minutes. Thirteen percent of the companies took only 10

minutes to complete the questionnaire which was the shortest time while 5 (21%) of

the companies took more than an hour and the longest time taken was 120 minutes.

Figure 7.15 Summary of responses on the questionnaire

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DISCUSSION

An efficient review allows the regulatory authorities to fulfill their public health

mission to ensure that safe and effective medicines are made available to patients in a

timely manner and allows for the efficient use of resources. Patients benefit from the

timely access to safe and effective therapies while pharmaceutical companies are able

to market their products sooner and generate revenues (Booz Allen Hamilton, 2008).

The regulatory challenge is to allow access to the safest and most effective

pharmaceutical products in the shortest possible time with the highest degree of

certainty (Alder, 2001). In the GCC states, pharmaceutical companies can choose

whether to register new products via each regulatory authority individually or via the

central registration system and the length of the expected review time will influence

this decision. Therefore, evaluating the pharmaceutical industry‟s views about the

advantages and disadvantages of the GCC-DR system and how this has impacted the

speed of the marketing authorisation time of their products in each Gulf State was

essential.

Pharmaceutical companies were able to provide critical information on the strengths

and weaknesses of the CP registration system. Based on this experience, only 13

companies surveyed preferred the CP registration system, of which nine were generic

companies. The main reasons for choosing the centralised registration system over the

national system include:

The ability of the pharmaceutical companies to meet the requirement of GCC

tender specification.

The convenience of the system,

An improvement of patients‟ access to safe and effective medicines in the GCC

region.

The central registration team is more accessible and easier in communication,

The companies‟ strategy and economic-related factors.

The pharmaceutical companies which preferred the national system stated that their

product strategy was aligned to the registration in selected GCC states for the

following reasons and hence their preference:

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Timeline of registration.

Experience with national system.

Concern over possible rejection by GCC-DR.

More transparent and communication easier with local national regulatory

authorities.

Limited number of GCC-DR annual meetings.

However, despite the majority of the companies‟ preferences for a national

registration, the companies indicated that the CP has a better and efficient registration

system as compared to the national system. The companies agreed that the CP

provides better scientific opinion/outcome than the national system and that the CP

provides consistent evaluations as compared to the national system. The companies

indicated that through harmonisation of the processes, which would entail one

approval procedure, one set of documents for the entire approval process and one file

with the same format for one submission, the procedure is much simpler and less

complicated.

This saves time and effort and promotes transparency. Furthermore, a medicinal

product can be available to all GCC states at the same time once it has been approved

centrally. This also facilitates the registration of manufacturing sites in one step and

hence, reduces the burden on internal company resources. However, the time

consuming procedure and costly process coupled with unclear feedback and lack of

direct communication between the GCC-DR and the companies are some of the major

issues that hampered the CP registration system. The absence of guidelines leads to

inconsistency and therefore some radical differences occur at national levels. Many of

the documents submitted for the GCC-CP are requested again at a national level and

some GCC countries do not approve the product for distribution even after attaining

GCC-DR registration. Moreover, committee meetings held only four times a year is

insufficient to address all the product registration issues which results in further

delays.

Although more than 60% of pharmaceutical companies stated that it took more time to

register their products through the centralised system, they still felt that the GCC-DR

Centralised Procedure is the way forward for several reasons:

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By registering their products at GCC level they would have gained access to

seven markets in the GCC states.

The CP leads to the harmonisation of the procedures at the national level and

better quality scientific opinions.

The current centralised system provides consistent evaluations in comparison

with national evaluation.

The majority of these respondents indicated that electronic submission and

automation of some of the processes could assist in simplifying the Centralised

Procedure and hence shorten the whole process. Others indicated that the technical

evaluation could be simplified by relying on documents submitted to the GCC since

these were the same documents already submitted and approved in the US/UK and

other reference countries.

Pharmaceutical companies in general were satisfied with the quality of the GCC-DR

scientific opinions despite the hassle and the issues faced in getting their products

registered through the Centralised Procedure. In addition, the pharmaceutical

companies were satisfied with the efficiency and effectiveness of the GCC centralised

pharmacovigilance procedures as the GCC-DR, through this procedure, has monitored

Adverse Drug Reactions (ADR) of medicines rapidly.

All the companies indicated they were satisfied with the level of transparency of the

Centralised Procedure. They cited that the GCC-DR were open in their

communication, and it was easy to meet the central organization team member. They

were willing to simplify the issues, had great understanding and there was a high level

of transparency in the GCC executive office. However, there is still room for

improvement in the follow-up of the application process. Generally, the majority of

the companies indicated that they were satisfied with the relationship that they had

established with the Registration Department of the GCC-DR. They suggested that

increasing the sharing of knowledge through training, seminars and workshops could

promote more interactions between the companies and the GCC-DR authority

especially in discussing changes to regulations and procedures. This will significantly

improve the relationship between companies and GCC-DR authorities and can

contribute more in providing healthcare benefits to GCC States. The companies also

186

suggested that there should be an increase in the number of meetings and communications

between the GCC-DR committee and the pharmaceutical companies. Through openness

and regular communication with the companies and having open meetings to define

companies needs, the relationship between the two organisations would be improved.

This would also promote consistency in decision-making and provide transparency and a

clear justification should there be any rejections in the future. In addition, they suggested

that providing electronic online services would greatly facilitate communications with the

GCC-DR and expedite information requests. Pharmaceutical companies also agreed that

the pharmaceutical industry can influence the GCC-DR procedure through knowledge

sharing, interactions and collaboration as a partnership basis. Through such activities, the

pharmaceutical companies could provide support at any level through their worldwide

experience with authorities and regulators. The pharmaceutical companies could

contribute in drafting and refining guidelines and the GMP inspection system to make

them more effective and efficient. They could also assist the GCC-DR in streamlining the

procedure in order to improve and expedite the registration process.

Finally, the GCC authorities are facing an increasing number of pharmaceutical

companies who are demanding more efficient, effective and transparent regulatory

services. This places a significant pressure on the Gulf States to improve the quality of the

regulatory review process as well as to expedite the marketing authorization of

pharmaceutical products without affecting the quality of the new medicines. The GCC-

DR challenge in the beginning was to convince companies to consider submitting their

dossiers to the centralised procedure. The submission process is voluntary as GCC-DR

cannot implement a compulsory system until the required level of standardization in the

regulatory review systems has been reached. However, pharmaceutical companies still

have mixed feelings about whether they can gain faster marketing authorization through

the national regulatory systems or the regional centralised system (Al Essa, 2011). After

all, the goal of any pharmaceutical company is to complete the registration requirements

and gain access to the national GCC markets in the shortest possible time. In the end, two

approval routes, national and centralised, are permitted to exist side-by-side in the GCC

region. But for the centralised system to dominate, member states should seek ways to

increase their collaborative efforts to bring their systems closer towards standardization

that would facilitate the regional registration process and maintain patients‟ access to safe

and effective medicines within a reasonable time frame.

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SUMMARY

The pharmaceutical companies who responded to the survey were able to provide

critical information on the strengths and weaknesses of the CP registration

system.

In general pharmaceutical companies were satisfied with the quality of the GCC-

DR scientific opinions despite the difficulties and the issues faced in getting their

products registered through the CP.

The participant companies were satisfied with the efficiency and effectiveness of

the GCC centralised pharmacovigilance procedures as the GCC-DR, through this

procedure, rapidly monitors adverse drug reactions.

All the companies indicated they were satisfied with the level of transparency of

the CP as the GCC-DR were open in their communication, it was easy to meet the

central organisation team member, they were willing to simplify the issues and

had great understanding.

The GCC-DR has a significant advantage as the product could be promoted faster,

easier and is highly recognisable in the seven GCC States.

The major disadvantage of the CP as compared to the national system is the time

and the expense involved in the process, followed by the inconsistency of the

process and the insufficient number of meetings. The companies also stated that

the need to re-submit product files at a national level after approval at the

Centralised Procedure is a further disadvantage.

The study confirmed that although more than half of the 30 pharmaceutical

companies preferred the national registration system as compared to the GCC-DR

Centralised Procedure, they agreed that the CP is the way forward for the future

as it will bring about harmonisation of the registration process, quality scientific

opinions and faster access to the GCC market.

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CHAPTER 8

The Gulf Centralised Procedure- A

Comparison between the Experiences of

Regulatory Authorities and Pharmaceutical

Companies: a Proposed new model

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INTRODUCTION

The Centralised Procedure was designed to improve the operation of the „Single

Market‟ for medicinal products, the avoidance of duplication of scientific evaluation

and the reduction of the administrative burden. Apart from these, product safety

enhancement and harmonisation are also important for this region. However, the

situation in the Gulf Centralised Registration procedure is complex because each state

has its own government, constitution, legislation, regulatory requirements and

healthcare systems, as well as differences in history and medical practices.

Today regulatory authorities are thinking in terms of Global and Regional themes, for

example the European Medicines Agency (EMA), the African Regulatory

Harmonization Initiative (AMRH), and the International Conference on

Harmonisation (ICH) for Europe, Japan and USA. However, such efforts are not risk-

free due to the influence of regional groups in pursuing harmonisation of drug

registration. In addition, more stringent registration requirements may displace

substandard medicines from the market.

The Ministers of Health in most of the Gulf States have expressed their doubts about

the ability to secure the expertise required for registration while at the same time there

is the fear of losing their sovereignty to the centralised authority (A. Rahman, 2005).

The successful development and registration of a medicinal product requires effective

dialogue between the pharmaceutical industry and the health authorities. For the

pharmaceutical industry, good communication with the health authorities is essential

during the entire lifecycle of a medicinal product, which include the registration

procedure and the subsequent maintenance phase (Heidenreich, 2004). The main goal

of both the pharmaceutical industry and the health authorities is to establish a positive

benefit/risk ratio and an appropriate benefit/risk management system for medicinal

products. Pharmaceutical companies should contact the health authorities at an early

stage in the development in order to achieve this goal. Early and frequent dialogue

between these two stakeholders can build a good relationship between the future

assessors of the marketing authorisation applications and the responsible managers of

the company. This may rule out problems and issues with the development of the

product and thus reduce the risk of an application been rejected.

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The result will be more rapid access to essential priority medicines, including

important new treatment options such as generic fixed-dose combinations of assured

quality and affordable prices by the communities and patients in Gulf States. National

drug regulatory authorities need to be better equipped to register medicines in a cost

effective and timely manner and this will lead to increased efficiencies across GCC

Countries. Capacity building will enhance the quality of the registration decision,

whilst streamlined processes and improved information management lead to effective

medicines control. As a result drug regulatory authorities may enjoy substantial

savings and increased patient reach with generic equivalents (in the context of high

volume and high value essential medicines. Beyond this, Governments could enjoy

additional economies of scale via pooled procurement which is only possible when

the same medicine is registered across all participating countries.

OBJECTIVES

The main objectives of this comparison were to:

Identify the similarities and differences between the experiences of regulatory

authorities and pharmaceutical companies with the Gulf Centralised

Procedure.

Develop a new model for the GCC-DR based on evaluation and the outcome

of the centralized procedure.

Propose a business plan which would enable the implementation of the new

model

METHODS

An assessment of the Centralised Procedure was carried out with two groups of

stakeholders in the GCC. The first study Gulf Assessment of Centralised Procedure

(GACP) evaluated the experience and opinions of all seven Gulf regulatory authorities

with the GCC Centralised Registration. The second study Companies Assessment of

Central Procedure (CACP) evaluated the experiences and views of pharmaceutical

companies with respect to the centralised registration review process. In this chapter,

a comparative analysis between the GACP and the CACP is presented to highlight the

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issues and challenges faced by these stakeholders as a prelude to the

recommendations to be made to the GCC-DR. Information from chapter 5, 6 and 7

was used to develop the new GCC-CP model and proposed business plan which

would help to implement the new model.

RESULTS AND DISCUSSION

The results of this comparison will be presented in three parts:

Part I: The Similarities and Differences between the Experiences of the Drug

Regulatory Authorities and the Pharmaceutical Companies.

Part II: The proposed model for GCC-CP.

Part III: The proposed business plan which would help to implement the new GCC-

CP model.

Part I - The Similarities and Differences between the Experiences of

the Drug Regulatory Authorities and the Pharmaceutical Companies

At the introduction of the GCC-DR system in 1999, government officials were

concerned about losing sovereignty to the centralised authority (Hashan, 2005). The

central registration system has faced criticism for some aspects and approval for

others from both the member states of the centralised authority and the

pharmaceutical companies dealing with the system. An interesting development

which contributed to the improvement of the GCC-CP was the appointment of

“Cameron McKenna and Andersen Consulting” to audit the EMA's centralised and

decentralised drug registration procedures. An EMA audit survey mandated a review

of that agency's activity within six years of its inception.

The report of this survey namely the Evaluation of Community Producers for the

Authorisation of Medicinal Products was published in October 2000. It was based on

interviews with and/or questionnaire responses from trade associations, national drug

registration authorities, professional and patient associations, national ministries with

interests in drug approval and pharmaceutical companies. The audit report contained

the following summary of survey responses:

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1) The centralised and decentralised procedures are both perceived to have

contributed to the creation of a harmonised community market for

medicinal products.

2) There is some criticism of particular aspects of both systems. However, in

general, the two systems provide a strong foundation for future progress to

a harmonised and efficient regulatory environment. Because of their

different attributes, there is a strong desire on the part of both applicants

for marketing authorisations and the competent regulatory authorities to

maintain the parallel systems.

The survey examined many aspects of both the centralised and mutual recognition

procedures. The auditors did not limit their research to the EMA's activities, but they

investigated member states' response to EMA decisions. This audit survey examined

the level of satisfaction with the Centralised Procedure. Of the 32 companies that had

obtained marketing authorizations by this route, 88% were satisfied with the system

and 3% was very satisfied. These results are identical to the outcomes of this study.

The member states regulatory authorities of EMA were more enthusiastic about the

Centralised Procedure with 73% being satisfied while 20% were very satisfied with its

operation. These results from Europe also mirrored the outcomes of this study in the

Gulf States.

A well coordinated, reliable centralised regulatory framework effectively reduces the

administrative burden and duplication of scientific evaluations by participating

member states. The companies believe that if this procedure was streamlined, was

faster and transparent it could be the system of choice. As the documents for a

medicinal product are submitted as a common single registration, this results in cost

saving and an efficient follow up opportunity in all the seven Gulf States. At the

beginning of 2014, the GCC-DR will initiate the CTD electronic submission (as NeeS

[Non-eCTD electronic Submissions] format), which is currently implemented by

internationally recognised agencies and as from January 2015 only the eCTD format

will be accepted. This approach is useful in that it assists the pharmaceutical

companies in understanding the rules of the submission process and thus helps both

the industry and the authority to make better decisions (TGA, 2009). The findings

from this study highlight the ten years achievement of the Centralised procedure and

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its future potential as identified by the health authorites as well as the pharmaceutical

companies. The pharmaceutical companies shed some light on the advantages and

disadvantages of the centralised system which were similar to the views of the

national regulatory authorities of the member states, although in some ways they were

different. Both the regulatory authorities and the pharmaceutical companies agreed

that the centralised procedure is an effective system for authorizing the marketing of

medicinal products in all of the GCC countries in one procedure and is the way

forward, but there is room for improvement in the procedure and the follow ups.

With regard to submission preference the majority of the pharmaceutical companies,

which took part in this study, prefered the review at a national level mainly due to

their experience with the national regulatory authorities, therefore making it easier to

gain market authorization. The long duration of the CP process contributes to the

preference for the national submission as well as the fear of rejection by a centralised

authority. The preference of the pharmaceutical companies to apply to national

authorities is confirmed by the responses of the national regulatory authorities which

stated that the number of national applications was greater than those submitted to the

centralised authority adding to the workload of the national regulatory authorities in

addition to their CP workload.

Despite the preference of the pharmaceutical companies for national submissions,

they find the registration at the CP to be better and more efficient. Ease of

communication has been reported for both the national procedure and CP although

there is no direct access to CP by the pharmaceutical companies. Most of the national

regulatory authorities of the member states concur with the fact that the duration of

the process to obtain market authorisaiton through the centralised procedure should be

shorter to make it more appealing to applicants. The duration of the centralised

procedure could be shortened by several means which include increasing the number

of CP committee meetings per year which has been clearly recognized by both the

pharmaceutical companies and the national regulatory authorities. The lack of

resources, mainly human expertise on the side of national regulatory authorities,

contributes as well to the delays even though there is effective collaboration and

sharing of information between the national regulatory authorities. Recruiting external

experts can aid the national regulatory authorities with the shortage of human

expertise but there is a fear that this will impact the quality of the review. The demand

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for additional requirements by different national regulatory authorities adds to the

delay and length of the process. The most effective way is to optimise the process of

evaluation by the centralised authority by finding a more appropriate model.

According to the regulatory authorities‟ views, standardisation of the system would

also be a means to improve and facilitate the regional registration process and

maintain the supply of safe and effective medicines within a reasonable time frame.

The national regulatory authorities in the Gulf have found the shared experience, ideas

and knowledge at the centralised meetings to have enriched their own experience and

knowledge which is reflected in their performance at the national level. The clear

outcome of this collaboration and joint effort between the national regulatory

authorities produces an improved scientific opinion and a higher quality of decision-

making. Pharmaceutical companies have also indicated their agreement with this

where they found consistent evaluation of submission and a better scientific opinion

received from the centralised authority than from the national regulatory authorities

leading to a more efficient system.

One major aspect of CP approval reported by both the pharmaceutical companies and

the member states is the centralised pharmacovigilance procedures and reporting

system which are efficient and effective. In addition, member states of the centralised

authority find the GCC guidelines to be sufficient and appropriate for their intended

purpose. On the other hand, pharmaceutical companies, submitting to the centralised

authority, struggle due to the absence of appropriate guidelines leading to

inconsistency. Also there are differences when accessing the market at a national level

such as re-requesting documents already submitted for the CP or not even approving

the product for distribution after attaining GCC-DR registration.

Certain aspects of the registration procedure can be modified in order to move

forward and improve the quality of the experience. Both the national regulatory

authorities of the member states and the pharmaceutical companies have agreed that

the use of electronic on-line submissions to the centralised authority, as well as

electronic communication between the member states, is one way to expedite the

process. This is the current method implemented in the recognised established

authorities worldwide such as EMA and FDA. Further, a recognition of the

assessment by established mature regulatory authorities through implementation of

the verification procedure is a means of improving the process and easing the burden

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of the high workload on the national regulatory authorities and for the pharmaceutical

companies as well. Harmonisation of requests and clarifications sent to the

pharmaceutical companies is yet another way agreed by both the pharmaceutical

companies and the national regulatory authorities. The national regulatory authorities

identified the need for training, seminars and workshops to improve the experience of

their expert staff. Pharmaceutical companies have suggested the same where the

additional interactions between pharmaceutical companies and the national regulatory

authorities would improve the overall knowledge of the national regulatory authorities

especially as the pharmaceutical companies have worldwide experience. Also it would

further enhance the relationship and communication between them. The

pharmaceutical companies even suggested helping to draft, improve and refine

guidelines including GMP. One of the key concerns, as highlighted by the companies,

is the limited number of committee meetings per year. The quarterly meetings to

validate the pharmaceutical products are clearly insufficient to meet the increasing

demands for product registration and approval. The companies recommended that the

frequency of the GCC – DR committee meetings needs to be at least 8 per year or

every 45 days. In addition, sub-committees could be formed with more frequent

meetings to handle specialised matters such the registration of life saving products.

The companies recommended that the comments and opinions of the countries, where

the products have been registered nationally, should be considered when products are

being evaluated by the GCC-DR. In this way, the approval process would be

expedited and this would facilitate faster approvals at a national level after the

products have been approved by the GCC-DR. Over half of the companies supported

the GCC-DR procedure while five companies out of thirty prefered the national

registration system. The main reason companies move toward local registration is

because of the delay and queuing at CP. Nevertheless, the companies agreed that if

the GCC-CP improves it will increase its acceptability of the marketing authorisation

issued centrally in other markets. They also suggested the use of University

laboratories to speed up „product testing‟ against additional fees.

The only way to improve support for the GCC registration is to give some advantages

over the national registration for companies who choose this route. It is very

important to note that most companies are seeking to establish a single registration

system, either national or centralised, for their products. Dealing with two registration

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systems in the same region is impractical. For all these reasons, companies usually

adopt the most economically viable registration system that meets their corporate

objectives. In conclusion, figure 8.1 summarises the key issues to be consider in the

new proposed GCC model.

Figure 8.1: Key issues to be consider in the new proposed GCC model

Part II - The proposed model for GCC-CP

The time taken to register a pharmaceutical product differs from country to country

and from product to product. However, it is possible to complete the review process

within a reasonable time frame if the data are available and adequate. Many countries

have legislative maximum times allowed for the review of a dossier. For example, the

target time-frame for completing the review process in the EU centralized system is

210 days, although the clock is stopped if it is necessary to ask the applicant for

clarification or further supporting data (EMA, 2009). This compares to the median of 304

Enhance the relationship

and communication between the stakeholders

Standardizatio

n of procedures

Increase in the number of committee meetings

On-line

submission

Improve the outcome of the review

Registration time should

be shortened

Verification procedure is a

means of improving the

process

197

days taken by the US FDA (CIRS, 2013). Several challenges faced the GCC health

authorities to successfully operate the centralised system. Therefore, they encountered the

need for regulatory reforms during the last 12 years, in order to improve their individual

systems and to unify their procedures to expedited improved patients‟ access to high

quality medicines throughout the region. The GCC-DR challenge in the beginning was to

convince companies to consider submitting their dossiers via this procedure. The

pharmaceutical companies still have mixed feelings about whether they can gain faster

marketing authorization through the national regulatory systems or the regional

centralized system. After all, the goal of any pharmaceutical company is to complete the

registration requirements and gain access to the national GCC markets in the shortest

possible time.

It is crucial for the GCC states to identify the most prevalent driving forces for improving

the centralised procedure and to attract the pharmaceutical companies to use this system.

From the results of this study and the information in chapter 5, 6 and 7 a model can be

proposed based on the current GCC-DR centralised procedure (Figure 8.2) and taking

account of the comments in part I of this chapter. The model‟s main features are as

follows:

Maintain the main structure of GCC-DR centralised procedure.

Amend the parts that are time consuming in the current GCC-DR centralised

procedure.

Allow all member states to participate in the review process and the conclusions

reached in a timely manner.

Adopt an electronic system of review for the proposed model to overcome

infrequency of meetings and the possibility of all member states participating in

the review process in a remote manner.

Adopt electronic communication with applicants for deficiencies for improved

review process.

Adopt a clock-stop timing for the review process based on the automation of the

review process.

This model (Figure 8.3) is based on the current GCC review process. It maintains the

main features of the approval process namely receipt & validation, management of the

overall dossier review cycle, registration approval by heads of authorities and upholding

the independence and sovereignty of member states within the approval process.

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However, the proposed model eliminates the steps in the approval process which are time

consuming and present redundancy in the process. The main step to be eliminated relates

to the questions raised by member states following the review. Clearly this step raises the

question as to why member states would raise questions that are not highlighted by the

two reviewing authorities. This at best produces doubts regarding the review capabilities

of certain member states while at worst raises doubts about the GCC review process in

general. On one hand each member state must be allowed the possibility to state their

views regarding the application, while on the other hand there is a need to achieve review

time efficiency. To realize such a target the model proposed is as follows:

A. Receipt phase: Receipt of the application is carried out in accordance to the

published GCC guidelines for NAS‟s and EAS‟s. The applicant should request a

submission date for the application which would be provided by the GCC office. It is

of importance that the applicant would provide a statement that the application being

submitted has observed all the relevant GCC guidelines. This statement has a

functional effect on the clock-stop as it is quite frequently observed that applicants

submit partially completed dossiers, especially the local industry, making promises to

bring missing or complete data at a later date. The applicant must be held accountable

in such cases and this can only be done according to local laws if such documents are

provided, otherwise the receiving officer will usually be held responsible.

Furthermore, the statement will serve as time zero for the “clock-stop”. The receipt

process should be conducted at the GCC Executive Office and performed by GCC

staff. This phase is actually maintained as the current practice of application receipt at

the GCC office.

B. Validation phase: The validation phase may be critical for agencies like Health

Canada, US FDA or EMA, when many dossiers are submitted by the applicant

whereby the submission is screened to ensure that the data are complete and of

suitable quality for review. In this phase for the GCC-CP the requirements are

checked against the requested formal requirements. This should include the

administrative registration (reference number) and checks on legal requirements, the

status of the company, manufacturer etc. as well as a „checklist‟ validation of the

application content (e.g. technical sections, CPP status).

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Figure 8.2 The current GCC-CP registration system

211

Figure 8.3 The proposed model for GCC-CP

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Further checks on patent compliance are necessary and any contractual

arrangements such as contract manufacturing or licensing agreements are also

checked. The allocated clock-stop time for both processes of administrative and

legal formalities should be 30 days. The validation processes are carried out at the

GCC office. In effect the validation process should make sure that the submitted

application is in compliance with the formal requirements as stated in module 1 of

the CTD specifications together with further checks that all the required technical

data is provided. This phase is maintained as the current practice of application

validation by the GCC office.

C. Review phase: The scientific assessment stage is the major part of the review

process and requires considerable amount of evaluation of data relevant to the

safety, efficacy and quality of the pharmaceutical product. Therefore, it is

essential to focus the attention on providing the appropriate skill sets and the

facilities as well as establishing guidelines, SOPs, training and continuing

education programmes and the electronic handling of the review process to

implement the desired good review practices (GRPs). In the new proposed model

the scientific review should be overhauled to allow all member states to

participate in the review process in a one-step approach. This necessarily means

that steps (C), (D) and most of (E) of the current GCC model of practice are

merged into one step in the proposed model. In this phase, two committees are

established from all member states. Therefore each member state is represented in

each of the two committees to ensure the active participation of all states. The two

committees are as follows:

a. Clinical committee: this committee should consist of experts from the

member states and should be responsible for reviewing the clinical

requirements for both NAS‟s and EAS‟s dossiers. In effect this committee

is concerned with safety and efficacy/modules 4 and 5 of the approved

GCC CTD standard.

b. Technical committee: this committee should consist of experts from the

member states and should be responsible for reviewing and approving

API‟s and excipients in the formula as well as the finished product. This

committee is very similar to the EDQM committee in the EU in addition

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to the technical review committee in respective EU member states. This

committee would focused on module 3 of the GCC CTD standard.

The clinical and technical committees cover all aspects with regard to the safety,

efficacy and quality of the product while any legal aspect that may relate to the

product would have already been checked during the application validation

process. The clinical and technical committees approach to the product‟s review

compared to the two step approach of the current model would lead to

considerable time saving and review process efficiency and transparency. Each

member state would be able to state their approval or concerns during the review

process in that particular committee. A letter of deficiency relating to that

committee would be issued to the applicant with a time limit for the applicant to

respond. The committee‟s meeting time can be organised in a manner to allow for

the review of new applications while keeping about 30% of the meeting time for

replies to issued letters of deficiencies. The committees should meet at least once

a month to keep the process efficient and timely. The allocated clock-stop time

for both committees concurrently is 150 days. The tasks performed in the

committees are done primarily by members of staff from health authorities of the

member states and not from the GCC office staff.

c. Laboratory analysis: the required laboratory tests should be performed

concurrently with the application review process of both clinical and

technical committees. The allocated clock-stop time for the laboratory to

complete the required tasks is 120 days which is well within the 150 days

clock-stop time allocated for both clinical and technical committees. This

should be the default and implies that the work of both clinical and

technical committees and the laboratory is harmonized and synchronized

to complete the work within the 150 days time limit.

D. Approval phase: Once the two committees grant approval for their part as well as

the laboratory decision to approve the product, their respective decisions are

transferred to the head of authorities meeting to give the approval to issue the

registration certificate. If, for any reason, the heads of the authorities are

concerned regarding any aspect of the application they will issue a letter of

concern to the appropriate organisation which might be the GCC management

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staff, specified committee(s), the laboratory or the applicant. Once the concern is

answered then an instruction to issue the registration certificate is mandated. The

heads of authority‟s approval is to check that the approval process steps and an

adequate review is observed. This may represent a quality assurance task

performance to guarantee good review practices at the GCC office. The allocated

clock-stop time for this phase should be 30 days and the tasks are entrusted to the

heads of health authorities of the GCC member states. The heads of authorities in

this case should be considered as the approval council (head of agencies) and they

should meet, every month. The allocated clock-stop time for this committee is 30

days. This takes into account the meeting frequency of this committee making

sure that once the applications passes all requested formal and substantive

requirements the application‟s final approval by the heads of authorities shall be

compliant with the clock-stop. Once the approval is granted by the approval

council then the GCC office should issue the registration certificate for the

product under application.

In order for the above proposed model to function the following are required:

a. Clear guidelines for the review process are laid down by the council of

heads of authorities. Good review practices should be mandated in such

guidelines. The GCC should elect one authority to host a training academy

for all aspects related to the sciences and skills needed by the GCC and

member states staff involved in the review process.

b. Electronic management (Computerisation) of the whole process of the

review including an electronic review system which allows committees to

hold meetings, while each committee member is in their office, utilising

modern computer software and communication tools and devices. Using

modern meeting techniques will result in cost savings, process efficiency

and significant review time saving. Further electronic process

management will enable external experts to participate in meetings of the

various committees if required without the need to make travel

arrangements giving expert support to the work of the GCC reviewing

process.

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This new model would allow the GCC to adopt a clock-stop approach to the review

process. The GCC‟s main bottle neck is the “questions to the applicants” raised by

non-reviewing member states. This proposed model eliminates such a bottle neck

through the participation of all member states in the reviewing committees. The time

saving should allow GCC to promise 210 calendar days for NAS‟s and of course

fewer days for EAS‟s is expected, but at worst would be the 210 days.

However, adopting the clock-stop dictates that the applicant‟s expected response time

and date is indicated to the applicant. Failing to meet the response date by the

applicant should allow the GCC to remove the application from the review process

after warning, in order to reduce the review pipeline. Clear guidelines for the clock-

stop concept and the use of such a concept should be clearly documented and

announced.

The laboratory analysis requirement should be performed in a manner that eliminates

delays in the analysis process. This is based on member states laboratories declaring

their readiness to meet the clock-stop requirement and availability of time for

analysis. Even though each of Kuwait, Oman, UAE and KSA Quality Control (QC)

laboratories are well equipped for conducting analysis of pharmaceutical products,

member states should agree on accreditation criteria for QC laboratories in order to

officially identify that these laboratories are able to meet these accreditation criteria.

In addition, each member state with the ability to meet the accreditation criteria

should also be able to accommodate 120 days clock-stop to complete the assigned

task. Analysis tasks are assigned to laboratories that declare their ability to meet the

clock-stop requirements and tasks are given to member states laboratories in order to

give analysis tasks to member states laboratories in a fair manner. This would allow

all participating laboratories equal opportunities to contribute to the process of

product approval in the GCC system. In this way, laboratory tasks, assigned in this

model, would eliminate the long analysis time and undue waiting experienced

currently.

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Part III - A proposed business plan underpinning the implementation

of the new GCC-CP model

Quality management practices are an integral part of several established drug

regulatory authorities (eg. EMA, FDA) including governance configuration and its

business processes. These practices help to ensure that the agency operates to

consistently high levels of quality, efficiency and cost-effectiveness. In terms of

financial resources, it is worth investigating the impact of different budget structures

on performance across authorities (Anderson, 2007).

The agency charges a fee for processing applications from companies that want to

bring a medicine to the market. It also charges fees for services related to the

marketing of medicines in the EU in areas such as scientific advice, inspections,

renewals and variations and the establishment of maximum residue limits. The total

budget of EMA was 194.4 M€ in 2009 (EMA, 2010) and it is expected to be 239.1M€

in 2013. The budget process allows the EMA to cover its needs, mainly by fee

revenue which is subject to fluctuation.

The pharmaceutical industry considers EMA fees fair and appropriate „to the services

provided‟. On the other hand the US FDA's federal budget request for fiscal year (FY)

2012 totalled $4.36 billion (El Boghdady et al, 2012). About $2 billion of this budget

is generated by user fees and pharmaceutical firms pay the majority of these fees,

which are used to expedite drug reviews. Even though the procedures and

classifications differ considerably between EMA and FDA, the majority of

stakeholders consider both agencies provide high quality evaluations for their

products. It is noteworthy that the European pharmaceutical market size is 2/3 of the

US pharmaceutical sector.

The EMA fee structure (EMA, 2010) appears complex in comparison with the FDA

fee structure; there are specific cases for three different types of variations, such as

type Ia, Ib, and II, beyond extension, additional fees for specific strengths or

presentations, as well as referral fees. Several fee waivers favouring generics,

biosimilars, orphan and paediatric products, small and medium sized enterprises exist

in the EMA structure.

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On the other hand, the FDA levies establishment fees (US$, 457,200) every year from

the authorised drug manufacturers. In a similar fashion, FDA also gives fee waivers

like EMA, in special cases. Spending on medicines will reach nearly $1,100Bn in

2015 (IMS, 2012). The U.S. share of global spending will decline from 41% in 2005

to 31% in 2015, while the share of spending from the top five European countries

(Germany, France, UK, Italy and Spain) will decline from 20% to 13% over the same

period. In contrast to EMA, the FDA fee requirements include application fees for

previously filed applications or supplements , fees for designated orphan drugs or

indications ( both for prescription products or for a supplement) .

The FDA user fee programmes support the safe and effective review for human and

animal medicines, biological products, medical devices and the review of other FDA-

regulated products. User fees also allow FDA programs to achieve enhanced

premarket review performance. Other FDA user fees support the regulation of tobacco

products, the inspection of mammography facilities, the certification of color

additives and the certification of FDA-regulated products exported from the United

States. New user fees enacted by the FDA Food Safety Modernization Act support

essential food safety activities. The budget includes inflationary increases for FDA

user fee programmes, as authorized by law.

The Prescription Drug User Fee Act (PDUFA), enacted in 1992, authorizes FDA to

collect fees from companies that produce certain human drugs and biological

products. Since the establishment of PDUFA, user fees have played an important role

in expediting the drug approval process. On July 9, 2012, the President sanctioned

the Food and Drug Administration Safety and Innovation Act (FDASIA), which

includes the reauthorization of PDUFA through to September 2017. PDUFA V will

provide for the continued timely review of new medicines and biologic license

applications in the US. The new law ensures that FDA will continue to receive a

source of stable and consistent funding during fiscal years 2013-2017 and allow the

agency to fulfill its mission to protect and promote public health by helping to bring to

market critical new medicines for patients.

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Government support in the form of a budget is the method of financing employed in

most of the GCC States, however, only Saudi Arabia and Yemen are self-financed by

fees. Governments are committed to support the GCC authorities financially and

prioritise funding of the regulatory review process. In any case, arrangements should

be made so that the financial sustainability is maintained for continuous and effective

implementation of the various drug regulatory functions (Ratanawijitrasin, 2002).

The quality of the review process, the technological and scientific skills

improvements remain a limiting factor without Governmental support (Hashan, 2006).

The range of fees, however, varies significantly from country to country according to

the funding structure and the services provided by each authority. The relatively high

registration fees charged by the Saudi Food and Drug Authority (SFDA), compared to

the other GCC authorities, are related to the autonomous support of the SFDA for its

own practices, facilities and services through the direct access to the fees, rather than

being collected by the central government revenue as in the other GCC States which

may or may not be returned to the authority undertaking the work (Hill and Johnson,

2004).

The Yemen regulatory authority is an autonomous authority as well and therefore the

registration fees are slightly higher than those charged by the rest of the GCC States,

but considerably lower than SFDA probably to attract pharmaceutical companies to

the local market in Yemen. It is agreed by all the GCC authorities that in order to

improve the regulatory review process, the authorities need to increase their resources

such as the number of experts, developing the information technology structure and

establishing training and continuous education programmes.

Without appropriate funding, the authorities will always face difficulties in improving

their regulatory systems. It can clearly be seen (Table 8.1) the parity among member

states' fees ranging from no fees in Qatar to as high as USD 25,341 in Saudi Arabia.

This wide difference in the range of the requested fees at national level from each

member state will cause those with higher national fees to resist the GCC Centralised

Procedure.

218

Table 8.1: Registration fees in the GCC States

*The proposed fees structure calculated according to the ratio of current national fees to the total fees for all member states in addition to 10% as administration fees. (The basic fees in EMA for a single strength= 274,400 Euro) (FDA New Drug

Application (With Clinical Data) fees for 2014 fiscal year (FY) =$2,169,100).

It is recommended that if the proposed model is implanted then each member state

should decline their national fees in favour of GCC-CP fees and that the GCC-CP fees

should be shared amongst member states where each share is calculated according to

the ratio of current national fees to the total fees for all member states in addition to

10% as administration fees. For this model to be feasible in the future, the overall fees

of the GCC-CP must be increased. The increased fees would allow member health

authorities to benefit from these application fees and for tasks they perform during the

application approval process. Further to the above, the fees for analysis should be

awarded to the assigned QC laboratory of the member state performing the analysis

task. Training is a key element for capacity building for the success of the proposed

model. Training should be carried out to achieve higher performance with improved

efficiency for member states for the review of GCC-CP applications. The training fees

should be awarded to the member state hosting the training activity. The comparison

of the views from pharmaceutical companies and regulatory authorities has identified

the most important outcome as the desire for improving the GCC centralised

procedure model.

Bahrain Kuwait Oman Qatar Saudi Arabia UAE Yemen GCC-

CP

Proposed

GCC-CP

fees

Company

Registration

5 BD =

USD 13.3

250 KD =

USD

887.2

100 OR =

USD

259.7

NO

FEE

(ONLY

INSPECTION

FEE)

1000 DH

=

USD 272.3

3000 USD

10000 SR

=

USD 2,667.5

(ONLY INSPEC-

TION

FEE)

Products

NASs

5 BD

= USD

13.3

100 KD

= USD

354.9

75 OR

= USD

194.8

NO

FEE

95,000 SR

= USD

25,340.8

1000

DH =

USD

272.3

1500

USD

10000

SR =

USD

2,667.5

USD 30,4444*

Products

EASs

5 BD

= USD

13.3

100 KD

= USD

354.9

75 OR

= USD

194.8

NO

FEE

40,000 SR

= USD

10,669.8

1000

DH =

USD

272.3

1500

USD

10000

SR =

USD

2,667.5

USD 14,305*

219

SUMMARY

Agencies and companies agreed that the centralised procedure had

contributed to an effective system for authorising medicinal products in the

GCC by providing the best possible scientific opinion for the quality of CP

decision-making as compared to the national system.

Enhancing sufficient resources like qualified and trained experts together with

technical facilities would improve the quality of the GCC regulatory

performance.

It is crucial for GCC states to identify the most prevalent driving forces for

improvement to the GCC centralised procedure such as on-line submissions

and an increase in the number of committee meetings in order attract

pharmaceutical companies to use this system.

Quality management practices are an integral part of several established drug

regulatory authorities and its business processes. These practices help to

ensure that an Agency operates to consistently high levels of quality,

efficiency and cost-effectiveness.

The overall fees of the GCC-CP should be increased in order to allow member

health authorities to benefit from application fees and for tasks they perform

during the application approval process.

The comparison of the views from pharmaceutical companies and regulatory

authorities has identified the most important outcome as the desire for

improving the GCC centralised procedure model.

211

CHAPTER 9

General Discussion

211

A systematic examination of pharmaceutical regulation and its environment across

countries can help shed light on a country situation, provide a new perspective on the

constraints facing it and suggest options for improvement. A comparative approach is

used in this study, on the grounds that countries can benefit from learning from one

another. There are three basic reasons for conducting systematic comparisons between

countries (Booz Allen Hamilton, 2006).

Strategy development: comparing different ways of managing similar

problems can provide both positive and negative lessons, i.e. guidance on what

to do and what not to do. Comparing cross-country experiences is a useful way

of developing policy instruments for problem-solving in a particular country.

Understanding: comparing public policies can help improve understanding of

how government institutions operate within their environment and suggest

possibilities for improvement.

Interdependence: the interdependence of nations as reflected in international

agreements, regional political-economic groupings, bilateral treaties and

collaboration is constantly increasing. Accordingly, problems that occur in one

country can spill over into other countries more easily and rapidly today than

at any other time in history. Similarly, policies adopted in one country often

have important implications for others. In other words, knowledge about what

has occurred in other countries can help a country prepare for new challenges

of its own.

Making a positive decision about a pharmaceutical product requires careful weighing

up of the potential benefits and harms and the scientific complexity of such decision-

making should not be underestimated (Hill, 2004). From the authority‟s perspective,

success is the licensing of quality medicines to enable patients to have access in a

reasonable time frame without compromising safety and/or efficacy (Hashan, 2005).

Therefore, a thorough review is carried out by the assessors with particular emphasis

on the quality, safety and efficacy studies. The use of ineffective, harmful, poor

quality medicines can result in therapeutic failure, deterioration of the disease being

treated, resistance to medicines and sometimes death. It also undermines confidence

212

in the health review system, health professionals, pharmaceutical manufacturers and

distributors (Rago and Santoso, 2008). The complexity and challenges of the drug

registration system should not be overlooked. It is simplistic to believe that speeding

up the registration process will improve patients‟ access to quality, safe and effective

medicines. This is the industry‟s argument but neglects to take into account important

issues such as the quality of the review. Given the pressures that arise from the

legitimate business interests of the multinational pharmaceutical manufacturers, there

needs to be support for regional activities designed to ensure the quality in the

registration systems. This includes ensuring that there is adequate capacity to cover

the required resources and appropriate guidelines at a country level to assess and

control the quality of medicines.

Information sharing and harmonisation reduces workload and improves overall

regulatory performance. Harmonization is the value added that directs expert

knowledge and resources to functions that improve public and personal health and

facilitates access to essential medicines. Formation of effective networks among

national regulatory authorities participating in various harmonization initiatives

facilitates sharing of scarce resources; eliminates duplication of activities; saves

money for all; supports cooperation, collaboration and international understanding;

facilitates in building regulatory capacity and enhances public trust in regulatory

efforts.

The Gulf States faced significant challenges in dealing with their established

regulatory bodies who were reluctant to give up their independence to the newly

established GCC Central Drug Registration (GCC-DR) system (Al-Essa, 2011). The

idea of implementing a central registration system came originally from the

industrialised world, especially from the success stories of the European Medicine

Agency which encouraged gulf regulatory organisations to structure the central

registration system. The centralised process of the European Union drug regulatory

agencies under one roof resulted in the development of EMA which has attained

improved trust, transparency, communication and mutual recognition through the

unification process. The European approach to national and central procedures differs

greatly from that adopted in the GCC. The difference is conceptual and structural

which is reflected in the procedural aspects and furthered the outcome of the

213

European approach. The missing link in the comparison between the European

approach and the GCC approach is the following:

1. The European system was initiated based on the need for mutual recognition

between some member states. This lead to the mutual recognition procedure

between some member states such as UK, France, Germany, etc. The system

was further refined to the centralised procedure covering all member states. In

this evolution the European approach presented a coherent system for review

of medicinal products with standards acceptable to all member states. The

system has inherent flexibilities for applicants to choose the national route for

submission or the centralised procedure. Furthermore, the system allowed

applicants to switch from the centralised procedure to the decentralised

procedure. On the other hand, the GCC system evolved from the need for

communal procurement of medicinal products not from mutual recognition

needs. The foundation of the system is based on the GCC tendering procedure

rather than communal review system. The review standards and consequently

review quality leads to a non-harmonized system between member states. It is

this non-harmonized system that led to the difficulties expressed clearly by

GCC member state staff. In order to overcome this difficulty most member

states are advocating national harmonization with GCC-DR.

2. The European system of review and approval leads a formal grant of

marketing authorization for applicants without the need for follow up

submission by member states. In this regard the centralised procedure in

Europe represents a viable alternative to submission in multi-states in the EU

while the GCC-DR does not offer the same opportunity and applicants need to

go through the national procedure as well as following the central procedure

approval.

3. For a review system to be effective all elements of the review system must be

clearly defined through guidelines and procedure. One of the most important

elements in any review system is the pricing guideline and procedure. The

GCC-DR does not include the pricing element which is of course emanating

from the intended purpose of the GCC-DR being the unified route for

tendering in the GCC procurement of medicinal products.

214

4. The European Medicines Agency (EMA) has established systems of training

its own staff and extends it to the training of scientific experts. Training takes

into account entry level of review staff up to the continuous training of senior

reviewers. Even non-employed personnel have their own training (EMA,

2011). The main purpose of the training is to ensure the review process is

measured from different aspects namely effectiveness, efficiency, long-term

effectiveness on EU citizens, impact on EU internal market and on different

stakeholders (EMA, 2010). Training is the main tool to ensure a quality review

and the absence of a GCC-DR training system directly affects the quality of

the review procedure and consequently impacts all other features of the GCC-

DR system.

From the above it becomes evident that a comparison between EMA and GCC-DR is

not an objective assessment. Certain elements will look common between both central

procedures by virtue of them being central procedures e.g. the participation of

reviewers from all member states. However, for the EMA the criteria for a reviewer

appointment is based on review skills attested by EMA for any national member state,

while in the GCC-DR it is a formal procedure based on member state‟s discretion.

The anomalies between GCC-DR and EMA could render the comparison misleading.

The quality of the review process is a comprehensive and multifaceted concept

(Brown et al., 2002). Previous studies have concluded that it is not sufficient to

measure regulatory performance in terms of the speed of the approval process alone.

Maxwell (2004) indicated that: “Concern about quality of care must be as old as

medicine. But honest concern about quality, however genuine, is not the same as

methodical assessment based on reliable evidence”. Maxwell also identified six key

dimensions of the quality, and these are (1) Accessibility (is the service accessible in

terms of distance, time, and social barriers?) (2) Effectiveness (does the service

produce the desired outcome?) (3) Efficiency (does the service produce the desired

outcome with the least waste/at low cost?) (4) Equity (indicating the quality of access

to services) (5) Relevance to need (is the service appropriate to the needs of its users?)

(6) Acceptability (what is provided and the manner in which it is provided) (Moss,

2004). The quality of the regulatory review process, from the construction of the

dossier to the final regulatory decision must also be examined (McAuslane and Cone,

215

2006). The importance of implementing and maintaining Good Review Practices

(GRPs) are critical measures that need to be considered by the Gulf States to provide

consistency and to improve efficiency, clarity, and transparency of the review

process. It is important to adopt GRPs as standard processes through formal training

of the review staff (US FDA, 2009).

The GCC authorities were found to be carrying out a number of activities to bring

about continuous improvement in their regulatory review process. Various reasons

were stated for introducing quality measures into their activities but the most common

ones were to ensure consistency and efficiency and to minimize errors in the system

(Al-Essa, 2011). Therefore, quality systems should be regularly reviewed to ensure

that they are working effectively (Mallia-Milanes, 2010).

The purpose of this research has been to evaluate the regulatory review process in the

GCC central registration and its impact on patients‟ access to medicines in the GCC

States. The focus of chapter three was on evaluating the regulatory review process in

Oman in order to identify areas of improvements in the system. Chapter four analysed

the approval time over the period 2008-2010 in the GCC States. The evaluation of the

review times for New Active Substances (NASs) and Existing Active Substances

(EASs) in the GCC Centralised Registration system (January 2006 to December 2010)

was the focus of chapter five while chapters six and seven assessed the views and

experiences of the GCC regulatory authorities and pharmaceutical companies in order

to identify the strengths and weakness of the current GCC centralised procedure.

Finally, the similarities and differences between the experiences of regulatory

authorities and pharmaceutical companies with the Gulf Centralised Procedure and a

proposed new model for the GCC-DR was the focus of chapter eight.

The research began by thoroughly assessing the trend in the regulatory approval times

in Oman for the period 2006 to 2010. The findings showed that although there is an

increase in the approval time for all pharmaceutical company products, the median

approval time for the five year period was 117 days. This is within the time limit (4

months) which is fixed by the health authority for the overall registration time. Oman

is facing significant challenges reflecting the rapid advancement of regulatory

services with limited resources possibly influencing patients' timely access to

medicines. These challenges gave the regulatory agency no choice but to review and

update its regulatory practices. The ability to regulate medicines effectively is

216

determined by a number of factors including the availability of guidelines, good

written procedures and the provision of the appropriate resources to fulfill the

regulatory needs. The lack of resources can be compensated to some extent by

effective collaboration among countries and information sharing (WHO, 2008). The

Directorate General of Pharmaceutical Affairs and Drug Control (DGPA&DC) budget

is not separated from the MOH, so development is minimized, due to priority within

the government system. Increase in the registration fee and its use to develop the

authority could help to improve the quality of the review.

Another important aspect that needs to be highlighted in Omani regulatory practices is

the use of the verification model for the assessment of a new registration dossier. This

model is acceptable for the majority of applications if they are registered in countries

with recognized regulatory authorities. If not, it is critical to consider a thorough and

more specialized review for products which are not registered elsewhere and for

biotechnology and biological products. Singapore, for example, conducts a

verification review for all types of medicines which are previously authorized by at

least two reference authorities (e.g FDA, EMA), except for biological and

biotechnology products (Health Science Authority (HAS, 2011).

In a further study a downward trend was demonstrated in the median approval time

for most of the GCC States during 2008 to 2010. However, the approval time for all

approved products in the GCC States during this period varied from about 60 days in

Qatar and Oman (2009 and 2010), and to about 609 days in Saudi Arabia (2008).

There are many factors which can affect and explain the differences in approval time

in the GCC States. The main factor is the difference in the positions of milestones

within the approval process, for example, the analytical step starts with the scientific

assessment in Oman, Saudi Arabia, and Qatar (parallel procedure), but in Kuwait and

Bahrain the analytical step comes after the scientific assessment (sequential

procedure).

Regulatory approval times have also been influenced by the type of assessment

carried out by different authorities. Bahrain and Kuwait uses a verification review for

all types of products registered in countries with competent authorities. Saudi Arabia

performs a full review on all types of application while Oman and Qatar perform an

217

abridged review for all products. The GCC states should seek to increase the level of

funding to bring about the required expertise and resources to conduct a more

extensive review of important medicines, including biological and biotechnology

products. A clock stop is another important approach which is not fully enforced in

the GCC authorities to control the overall approval time. The EMA is obliged by the

regulation to reach a decision within 210 days, although the clock is stopped if it is

necessary to ask the applicant for clarification or further supporting data (EMA,

2009).

Furthermore, this research project investigated the pattern of total regulatory approval

times in the Gulf Centralised Procedure over the period from 2006 to 2010. It also

addressed the various factors which may have a positive or negative effect on total

approval times. During the five year period of the study (2006 – 2010), the median

approval time significantly increased due to several factors which included the limited

number of meetings by the GCC-DR and increased number of applications for

registration. Other factors that delayed the registration were the assessment review

process where two authorities are selected alphabetically to review the registration

dossier. In addition, the lack of a standard evaluation template for product assessment

leads to an increase in the correspondence which is sent to the sponsor in several

batches and at different times. It is recommended to have one standard assessment

template and rather than selecting the reviewing authorities alphabetically, the dossier

should be sent to all countries and all assessments combined into one final report on

which the final decision in the GCC-DR could be based. Other factors that could

speed up the registration process is an increase in the number of the committee

meetings and using information technology and e-mails in the communication

between the Executive Office and the companies.

The findings from this study also highlight the ten years achievement of the

Centralised procedure and its future potential as identified by the health authorites as

well as the pharmaceutical companies. Although, both the regulatory authorities and

the pharmaceutical companies agreed that the centralised procedure is an effective system

for authorizing the marketing of medicinal products, the pharmaceutical companies still

have mixed feelings about whether they can gain faster marketing authorization through

the national regulatory systems or the regional centralized system. After all, the goal of

218

any pharmaceutical company is to complete the registration requirements and gain access

to the national GCC markets in the shortest possible time (AL-Essa, 2011).

In the end, two approval routes, national and centralized, are permitted to exist side-by-

side in the GCC region. But for the centralized system to dominate, member states should

seek ways to increase their collaborative efforts to bring their systems closer towards

standardization that would facilitate the regional registration process and maintain

patients‟ access to safe and effective medicines within a reasonable time frame. It is

recommended that the comments and opinions of the countries, where the products have

been registered nationally, should be considered when products are being evaluated at

GCC-DR. In this way, the approval process would be expedited and this would facilitate

faster approvals at a national level after the products have been approved by the GCC-

DR. The only way to improve support for the GCC registration is to give some

advantages over the national registration for companies who choose this route. It is very

important to note that most companies require a single registration system, either national

or centralised, for their products. Dealing with two registration systems in the same region

is thought by some to be inefficient.

The GCC as a conceptual framework for harmonization among the member states has

been extended to areas like pharmaceutical procurement. In this regard the centralised

procedure was established as a step in the overall harmonization efforts of member states.

The GCC-DR is gaining momentum and importance for the private sector as reflected in

the responses of companies. Furthermore, the GCC-DR is contributing in a positive way,

especially in smaller member states although efficiency needs to be improved. Efficiency

can be clearly linked to the quality of decision-making during the review process and all

member states considered the GCC-DR review to be of the same quality as the national

review or better except for Saudi Arabia who considered the review quality as worse than

national review. Member states sought to find a solution to improve the review process by

utilising a standardised review template. This would avoid efficiency issues due to

requests for additional data. In addition raising the scientific and review skills of

participating staff from member states in the central procedure and by adopting clear

SOPs for the review process would be of benefit. Furthermore, harmonization of national

review guidelines and procedures within the GCC-DR would be an advantage as well.

Needless to say the positive influence of such harmonization will result in efficiency at

both national and central procedure level. For all these reasons, companies usually adopt

the most economically viable registration system that meets their corporate objectives.

219

The GCC-DR system can be better executed by the formulation of policies and guidelines

that are practical, concise and clear. A healthy interaction between regulatory agencies

and pharmaceutical companies at an early planning stage may boost the overall central

drug registration process. A competent registration process which is rooted in

transparency of procedures and unbiased scientific opinions would lead to a smooth drug

registration process among the GCC States.

Limitations of the study

As with any research there were a number of limitations including the following:

For the evaluation of regulatory review times in the Gulf States it was not possible to

obtain information of the review system or timelines for UAE or Yemen. This was

despite several e-mails and follow-up phone calls. Although for the sake of

completion it would have been ideal to have received data from both these States, it

did not have a detrimental effect on the overall conclusions.

The evaluation of the GCC Centalised regulatory review process only focused on

approved products. It would have been an advantage in reviewing the timelines to

have access to those products that were rejected, however, these were not available in

an electronic form and so would have necessitated identifying these manually. Again,

this would not have influenced the evaluation of the efficiency and overall

performance of the GCC-DR.

The evaluation of the pharmaceutical companies experiences with the GCC

Centralised Procedure was limited by the response rate of 30%. This was despite an

extensive follow-up of the companies who did not respond or who had limited

experience with the centralised system. In such circumstances, the problem is not so

much ending up with a low number, but rather the differences between responders

and non- responders.

221

Recommendations

As a result of this research there are a number of recommendations that can be made.

There is defiantly scope for improvement whether at national level or at the GCC-DR.

Although many, if not most, of the desired improvements are a common to all

member states some of them are specific to each member state. Common

recommendations for all member states include the following:

Adoption of harmonized regulations

Member states in the GCC-DR have collaborated to produce regulations that

govern the approval process at the GCC-DR. The regulations are in effect the

result of a common acceptance of the required standard for marketing

authorization of pharmaceutical products. It is logical for each member state to

adopt, at a national level, such regulations which would be the basis for greater

harmonization within the GCC-DR and among member states should mutual

recognition be contemplated between two or more states.

Training programmes

Common training programmes are needed for reviewers in all member states.

Such training programmes should provide the required knowledge and skills

for reviewers. In order for such programmes to be effective, acceptable criteria

for the attainment of training objectives must be agreed as well. This could be

at a national, inter-state or common for all GCC states. Only qualified trainees

should be allowed to progress to be official reviewers. Almost all developed

health authorities have similar programmes for training employees to be

reviewers and this is an essential element for any health authority.

Electronic process management

The adoption of computer based systems for task management is often absent

in most Gulf States despite the fact that they have adopted electronic

governance in their countries. Computerization is seen in almost all aspects of

life in the Gulf States and it is surprising that computer systems are not yet

used in many Gulf States for the regulatory review process. Computerizations

221

of process management remain one of the most challenging tasks for most, if

not all, GCC states. This task is assisted in that all member states and the

GCC-DR have adopted the CTD (Common Technical Document) standard for

dossier submission. Furthermore, the eCTD (electronic Common Technical

Document) standard is already published by ICH and should allow the Gulf

States to manage the computerization of the review process in an enlightened

manner.

Qualifying programs for Quality Control Laboratories (QCL)

In order to harmonize the standards for analytical procedures in each member

state, common standards must be agreed by member states for each state QCL.

This should be followed by appropriate training for all QCL staff and adopting

of common accreditation criteria.

Batch analysis

Like all Arab states, the GCC states perform release analysis for all submitted

products for approval. Further, the QCL performs release analysis for every

batch marketed. This places a burden on QCL in any country and prevents the

QCL from performing their main task of assuring the product‟s quality in the

market place. The GCC states need therefor to agree on the required function

of the QCL in member states which should be similar to the European

approach to QCL in European regulatory authorities.

Further recommendations are also suggested for the GCC-DR.

Adopt a new model for the regulatory review

As already outlined a new model is proposed for the GCC-DR. Irrespective of

whether the proposed model is acceptable or not, a new process model is

needed to improve the performance of the GCC-DR. Any model must take

into account the effectiveness and efficiency needs of the GCC-DR.

222

Proceed to full approval with pricing

For the GCC-DR to operate effectively the mandate foundation of GCC-DR

needs to be revised. The new mandate should state that the GCC-DR is the

way forward for approvals within the GCC states for medicine and health

products and this should include pricing of submitted products for approval.

Validation of authorized products in member states

To minimize the work load, the GCC-DR should adopt and validate approved

products already authorised in member states. In this regard the GCC-DR

should develop guidelines for such validation and seek member states

approval. The validation process should be a quality assurance process and

ensure that this is within an acceptable standard for member state.

There are also a number of recommendations for individual member state,

Harmonize regulations with GCC-DR

GCC-DR regulations should be adopted by each member state and this should

be a formality within the state legal framework.

Adopt mutual recognition

Member states should adopt mutual recognition with other member states with

a similar review system. This would allow the development of the GCC-DR

as an organisation similar to that of the European Medicines Agency.

Mutual recognition of QCL batch certificates

Member states should adopt mutual recognition procedure for QCL batch

certificates in order to reduce the work load and avoid unnecessary repetition

in samples analysis.

223

Exchange programmes for reviewers

Member states should adopt a programme of exchange for reviewers to allow

experience to be shared between member states.

Electronic processes

Member states should adopt the electronic management of processes and

documents. This will relieve the bottle necks in work performance including

the review procedures. Commercially available work flow systems, document

management system and electronic review systems are readily available and in

use by many health authorities worldwide but especially in Europe this has

been an established practice. Most European authorities including the

European Medicines Agency use validated software which is well accepted

and commercially available.

Future work

It would be of value to continue the evaluation of the Oman pharmaceutical

review process and analysis of the timelines for NAS‟s and EAS‟s for the

period 2011-2014. In addition it would be helpful to understand if there have

been any improvements in good review practice.

It would be advantageous to continue the evaluation of regulatory review

times in the Gulf States for the period 2011-2014 and to make sure that

responses are obtained from all states including UAE and Yemen.

As an evaluation of the GCC centralised procedure is fundamental to any

future model that might be implemented, it would be essential to update the

timeline data for products that have been reviewed between 2011-2014.

It would also be of value to repeat the evaluation of the Gulf States views and

experiences, as well as pharmaceutical companies with the GCC centralised

procedure over the past three years.

224

It would be of value both to the member states and the rest of the world to

understand from the seven Gulf States and the pharmaceutical industries what

are the benefits of this new proposed system as well as the challenges.

Conclusion

In this research the Gulf Cooperation Council centralised procedure for the approval

of pharmaceutical products was evaluated. The results demonstrated that the GCC-DR

centralised procedure has contributed to a better review process both at the GCC-DR

and national level. The GCC-DR needs to be revised and developed to an independent

marketing authorization granting authority providing applicants with one license that

covers all seven Gulf States. A new model for the GCC-DR CP has been proposed

which should resolve many of the difficulties facing the GCC-DR currently and

should improve its effectiveness and efficiency.

225

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Publications

238

Poster presentations

Al-Rubaie M., Salek, S. and Walker, S. (2011). Comparisons of the Gulf States and

Pharmaceutical Companies Perspective on the Effectiveness of the GCC

Centralized Procedure. Presented at the 47th

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Cooperation Council (GCC) Centralized Regulatory Review Process for

Pharmaceutical Products. Presented at the 48th

DIA annual Meeting, June 24-28,

2012. Philadelphia, USA

Oral Presentation

Al-Rubaie M., Salek, S. and Walker, S. (2011). Regulatory collaboration in the Gulf

Cooperation Council states. Presented at the Centre for Innovation in Regulatory

Science workshop, Evolving the regulatory review process: What are the features that

enable a transparent, timely, predictable and good-quality review, 6-7 December

2011, Kuala Lumpur, Malaysia.

Al-Rubaie M, Salek, S. and Walker, S. (2013). Ten years experience with the GCC CP

the challenges and opportunities. Presented at the 10th

Middle East Regulatory

Conference (MERC), 24-25 September 2013, Muscat (Oman).

Al-Rubaie M, Salek, S. and Walker, S. (2013). Oman regulatory review process.

Presented at the 10th

Middle East Regulatory Conference (MERC), 24-25 September

2013, Muscat (Oman).

239

Appendix 1

241

List of pharmaceutical companies respond to CACP

1 Abbott

2 Amriya Pharma

3 Apopharma Inc

4 AstraZeneca

5 B.Braun

6 CSL

7 Eli-Lilly

8 Glaxo Smith Kline

9 Glaxo Smith Kline Consumer Healthcare

10 Hospira

11 Hovid

12 Janssen

13 Jazeera Pharmaceutical Industries

14 Joriver

15 Kilitch

16 KSPICO

17 Leo Pharma

18 National Pharmaceutical Industries

19 Novartis Pharma AG, Basel, Switzerland

20 Oman Pharmaceutical Products

21 Pfizer

22 Pharmascience

23 Qatar Pharma

24 Ranbaxy

25 Reckitt Benckiser

26 Riyadh Pharma

27 Sandoz

28 SEDICO

29 Servier

30 SPIMACO